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GPs with an interest in cardiovascular diseases review papers of significance from research teams across the world

Prevention of cardiovascular disease with pravastatin
The primary prevention of cardiovascular disease
Fasting glucose and incident diabetes in older non-diabetics
How to find CKD patients for the quality framework
Depressive symptoms and the risk of stroke
Risk assessment in prevention of cardiovascular disease
Varied clopidogrel response and future therapies
The role played by statins in the prevention of cancer

Prevention of cardiovascular disease with pravastatin
Nakamura H, Arakawa K, Itakura H et al for the MEGA Study Group. Lancet 2006; 368: 1155-63

The MEGA study is a recently published primary prevention study. Men and postmenopausal women aged 40–70 years with hypercholesterolaemia (that is, total cholesterol concentration 5.69–6.98mmol/L) were eligible for entry into the study.

Major exclusion criteria were familial hypercholesterolaemia and a history of CHD or stroke. The follow-up was scheduled for five years, but the study continued for an additional five years to increase the number of events.

Eligible patients were randomly assigned to diet, or diet plus pravastatin, with treatment in the diet plus pravastatin group commencing with pravastatin 10mg. During follow-up, the dose could be adjusted by the treating physician, with uptitration to 20mg per day if the total cholesterol concentration did not decrease to 5.69mmol/L or less. This dose of pravastatin contrasts with that recommended in the UK (20–40mg).

All patients were advised to follow the National Cholesterol Education Program step I diet. Patients in both groups who had total cholesterol concentrations above 6.98mmol/L, even after alterations to the assigned treatment, could be switched to other aggressive treatments, including statin therapy. The primary composite endpoint was the first occurrence of CHD, which included fatal and non-fatal MI, angina, cardiac and sudden death, and a coronary revascularisation procedure.

Of 7,832 patients who were analysed, 2,223 consented and 1,013 refused to extend follow-up. Incidence of CHD was significantly lower in the diet plus pravastatin group than in the diet group (HR 0.67, 95% CI 0.49–0.91; p = 0.01).

The number needed to treat (NNT) to prevent one CHD event was 119 during the average 5.3 years of follow-up. The frequency of MI was also significantly lower in the diet plus pravastatin group than in the diet group (HR 0.52, 95% CI 0.29–0.94; p = 0.03; NNT 255). Treatment with pravastatin was associated with a lower incidence of stroke than diet alone, although this difference was not significant (HR 0.83, 95% CI 0.57–1.21; p = 0.33).

Although treatment with pravastatin was associated with lower total mortality than diet alone, this result was not significant (HR 0.72, 95% CI 0.51–1.01; p = 0.055.) The event rate in the MEGA study was 0.5 per cent per year in the diet-only group, compared to 1.8 per cent in the WOSCOPS study . The explanation is the sex difference: the participants were all male in WOSCOPS and 69 per cent female in MEGA, although it is mainly the men who had the effects.

The MEGA study supports other primary prevention studies by demonstrating that statins reduce cardiovascular events but as yet, have no demonstrable effect on cardiovascular mortality. Statins for the primary prevention of cardiovascular disease (CVD) are relatively ineffective even at standard doses
(NNT = 40 for cardiovascular events), demonstrating the fallacy of adopting more aggressive targets for cholesterol lowering in primary prevention.
- Dr Rubin Minhas is a GPSI in CHD and Medway PCT CHD lead

The primary prevention of cardiovascular disease
Thavendiranathan P, Bagai A, Brookhart A et al. Arch Intern Med 2006; 166: 2307-13

The role of statins in the secondary prevention of cardiovascular events and mortality is well established, but their value for primary prevention is less clear, so the authors of this paper undertook a meta-analysis of randomised controlled trials.

This was a two-stage process. The first stage consisted of the extraction of data from each individual study and the calculation of a result for that study (the point estimate), with an estimate of the chance variation (the CI).

The second stage involved deciding if it was appropriate to calculate a pooled average result across studies and, if so, calculating and presenting such a result.

Randomised controlled trials with a follow-up of one year or more and published between 1966 and June 2005 were identified. From each trial, demographic data, lipid profile, cardiovascular outcomes, mortality and adverse outcomes were recorded. Summary relative risk ratios with 95% CIs were calculated.
Seven trials with 42,848 patients were included. Ninety per cent had no history of CVD. The mean follow-up was 4.3 years.

Statin therapy reduced the relative risk of major coronary events by 29.2 per cent (95% CI, 16.7–39.8%, p <0.001), major cerebrovascular events by 14.4 per cent (95% CI, 2.8–24.6%, p = 0.02) and revascularisations by 33.8 per cent (95% CI, 19.6–45.5%, p <0.001). Most importantly, statins produced a non-significant 22.6 per cent relative risk reduction in CHD mortality (95% CI, 0.56–1.08%, p = 0.13) and there were no significant reductions in overall mortality (relative risk ratio 0.92, 95% CI 0.84–1.01%, p = 0.09). No increases in cancer or levels of liver enzymes or creatine kinase were observed.

In patients without CVD, primary prevention of CVD with statin therapy decreases the incidence of major coronary and cerebrovascular events and revascularisations but has no significant effect on CHD or overall mortality. Therefore, current evidence does not support any mortality benefit with statins in primary prevention; hence the arguments for systematic screening and initiation of statins in primary care are considerably weakened. There is no evidence to support lipid targets of 4mmol total cholesterol and 2mmol LDL cholesterol in primary prevention and ‘lower’ is not ‘better’. RM

Fasting glucose and incident diabetes in older non-diabetics
Barzilay JI, Davis BR, Cutler JA et al. Arch Intern Med 2006; 166: 2191-201

This study looks at the development of new cases of diabetes that may be related to medical therapy, in this case, in the ALLHAT study. Post hoc subgroup analysis was performed on the non-diabetic subjects receiving chlortalidone (8,419), amlodipine (4,958), or lisinopril (5,044) at the start of the study.

The inclusion criteria were age at least 55, BP >140/90mmHg and at least one additional CVD risk factor, such as previous MI, diabetes, or smoking.

The primary and secondary endpoints did not include diabetes, but along with CVD outcomes, did include the development of end stage renal disease requiring dialysis. The diagnosis of diabetes was made when fasting blood glucose was greater than 6.9mmol/L.

Fasting glucose was not measured as part of the trial, unlike, for example, in the LIFE study . It was only measured in 53 per cent of subjects during the study, although the number of subjects in the trial makes the results of this analysis important. Fasting glucose levels rose in all groups through the study.

Diabetes was more likely to develop in the chlortalidone group and the lowest odds for the development of diabetes were in the lisinopril group. Diabetes was more likely to develop with a higher systolic BP, higher initial blood glucose and higher BMI, all of which we would expect.

The development of diabetes was not associated with higher mortality or CHD risk, unlike the presence of diabetes at the start, although this was a short-term study and may not reflect the effect of diabetes on atherosclerosis progression.

The conclusion was that there is more risk of older patients on chlortalidone developing elevated fasting blood glucose levels than with other treatments. Although the study did not demonstrate increased risk of cardiovascular events related to this, it was never designed to demonstrate this outcome. It would seem inconceivable, however, that in the long term, this would not have an effect on clinical outcome.

The study would suggest the avoidance of chlortalidone, along with atenolol, in patients at risk of developing diabetes, such as the obese and those with impaired fasting glycaemia.
- Dr Kathryn Griffith is a GPSI in cardiology in York

How to find CKD patients for the quality framework
Hallan SI, Dahl K, Oien CM et al. BMJ 2006; 333: 1047

The most common causes of chronic kidney disease (CKD) in the UK are hypertension and diabetes. GPs are encouraged to measure creatinine levels in patients with these conditions and thus estimate eGFR and detect new cases of CKD, essentially those with an eGFR persistently lower than 60ml/min.

These patients are already subjected to medical intervention to reduce cardiovascular risk and the aim of groups such as the Kidney Disease: Improving Global Outcomes group is to improve outcomes and care for all people with CKD.

The aim of this study was to compare strategies for detecting patients with CKD by inviting all residents of a county in Norway, aged 20 or over, to attend for assessment, including creatinine estimation. Overall, 70.6 per cent did so and were followed from 1995 to 2004. Nine models of screening were compared. Screening only those with hypertension (11 per cent) and diabetes (3 per cent), for example, would detect 44.2 per cent of those found by screening the whole population. However, this method only screened 12 per cent of the population and 5.9 patients were screened to find one case. By adding CVD,
57.5 per cent were found.

If those with hypertension and diabetes, and in addition, those over 55, were screened, 93.2 per cent of all cases were found by screening 37 per cent of the population, screening 8.7 subjects to find one case. This method detected the most cases without screening the whole population.

Follow-up of subjects for a mean of eight years showed that of those with eGFR 45–59ml/min, 99 per cent did not progress to end-stage renal disease (ESRD) and 98 per cent with eGFR 30–44ml/min, which is good news for our patients with CKD.

Of those with eGFR <30ml/min, however, 20 per cent did progress to ESRD. Those most likely to progress were men over the age of 70 with hypertension and diabetes.

This study confirmed previous studies showing that those patients with eGFR <30ml/min have a four times higher risk of dying from cardiovascular causes than developing ESRD.

The study has some flaws, in that diagnosis is made from only one blood test, while the recognised definition of CKD requires an abnormality on tests at least three months apart. It is also unclear how complete the follow-up data are and this may underestimate the outcome.

The article is supported by an editorial in the same issue, which queries the value of screening for CKD when there are so many unanswered questions. For example, what are the socio-economic consequences of a low eGFR? How do values change with age? If the evidence for treatment is largely based on ESRD or those referred to renal physicians, what is the optimal treatment for elderly patients with eGFR 55ml/min?

The editorial’s conclusion is to continue to case-find in patients with hypertension and diabetes, to treat diabetes and CHD with evidence-based treatment (ACE inhibition) and to treat hypertension to targets, reducing the progression of CKD. KG

Depressive symptoms and the risk of stroke
Salaycik K, Kelly-Hayes M, Beiser A et al. Stroke 2007; 38: 16-21

Depression has long been associated with an increased risk and rates of CVD, especially in the elderly. Both depression and stroke are more common in the elderly, but there is no conclusive data on the link between depressive symptoms and cerebrovascular events in the community.

A team of researchers from the Boston University School of Medicine has evaluated whether there is an association between depressive symptoms and the risk of stroke or TIA in 4,120 Framingham Heart Study participants aged 29 to 100 years with up to eight years’ follow-up. The participants had their depressive symptoms and incident stroke/TIA assessed using a depression scale and diagnostic criteria for stroke/TIA.

The researchers concluded that patients under the age of 65 who present with depressive symptoms have an increased risk of stroke or TIA but the risk is not relevant in subjects over that age. Antidepressant therapy did not affect the risk of developing a stroke/TIA associated with depressive symptoms.

Interestingly, patients with depression tend to take low levels of exercise, usually smoke and have an unhealthy diet. All these are factors that might increase the risk of stroke/TIA.

This is the first community-based study that assessed the over-65 and under-65 groups separately and documented the association between depressive symptoms and stroke risk in under 65-year-olds.

More research is needed to understand the mechanisms leading to stroke in a younger population with depressive symptoms. Meanwhile, it is important to think about the risk of stroke in those individuals under the age of 65 presenting with depressive symptoms and consider primary stroke prevention.
- Dr Tim Holt is a GP and clinical lecturer at Warwick Medical School

Risk assessment in prevention of cardiovascular disease
Brindle P, Beswick A, Fahey T, Ebrahim S. Heart 2006; 92: 1752-79

This systematic review demonstrates that cardiovascular risk assessment tools, despite their popularity, have little research evidence to support their widespread use in primary prevention.

The vogue for opportunistic risk assessments (recommended in 2005 by the Joint British Societies) lacks a firm evidence base to justify its costs and resource implications. The authors found only four randomised controlled trials testing the effects of risk prediction tools on health outcomes or clinical behaviour, and little evidence of benefits.

The reason for this lack of impact may be twofold. First, the Framingham-based algorithms currently recommended are not well calibrated to modern populations, tending to overestimate risk generally in the UK, but underpredicting in deprived or higher-risk ethnic minority groups.

The other problem involves the use of the algorithm as a tool in clinical practice, because much depends on its impact on clinician behaviour and patient choices. Progress on these issues might come from the inclusion of additional information on ethnicity and deprivation, both becoming available in primary care databases, and the integration of the risk equation into the clinical environment in such a way that clinicians actually use it effectively for those most likely to benefit. TH

Varied clopidogrel response and future therapies
O’Donoghue M, Wiviott SD. Circulation 2006; 114: e600-6
The use of antiplatelet agents including clopidogrel is central to the management of patients with acute coronary syndrome. This article highlights the variability in the response of individuals to standard dosing schedules.

This arises from variable absorption of the oral pro-drug, its conversion to pharmacologically active metabolites, and in variable tissue responsiveness due to genetic polymorphisms.

A case vignette is given, describing how apparently successful insertion of a drug-eluting stent was followed several days later by occlusive stent thrombosis, despite adherence to the recommended protocol, a scenario carrying a high associated mortality. A further problem is the relatively long onset of action of clopidogrel in this life-threatening situation. Possible solutions include tailoring the prescribed clopidogrel dose to measures of platelet responsiveness in the individual patient.

However, the complexity of the assay process would require significant work to ensure standardisation between laboratories. Three antiplatelet agents, discussed in this paper, are becoming available that might produce less interpatient variability, and/or more rapid onset, all of them blocking the same P2Y12 receptor as clopidogrel.

As far as clopidogrel dosing is concerned, one size does not fit all. This variability may result in serious complications, but it is encouraging that a range of potentially superior agents is known and already at the phase III stage of clinical trials. TH

The role played by statins in the prevention of cancer
Setoguchi S, Glynn RJ, Avorn J et al. Circulation 2006; 115: 27-33

Some observational studies have suggested that statins may protect against certain cancers. However, most randomised trials and meta-analyses report either a slight increase in risk or no effect on cancer risk.

This latest research, a US cohort study involving 24,439 ‘typical’ older patients initiated on statins and 7,284 initiated on glaucoma drugs as a comparison, concludes that statins are unlikely to significantly affect cancer risk either way.

The characteristics of patients in the two groups were similar, although statin users were slightly younger and used services more often. Mean follow-up was 2.9 years, with the longest being 8.4 years. The researchers found incident rates of colorectal, lung and breast cancers in both groups to be similar to those among the general population. TH

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