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On The Pulse - September 2018

On The Pulse

Tertius Lydgate

Friday, 28 September 2018

Statins for primary prevention of cardiovascular events
Cardiovascular disease (CVD) is the leading cause of death globally with older populations at greater risk. Evidence suggests that statins are useful in those aged over 65 but little data is present for those aged over 74. A retrospective cohort study in The BMJ set to identify whether statin treatment is associated with a reduction in CVD and mortality in old and very old adults with and without diabetes. They cohort included 46,864 participants (mean age 77 years; 63% women; median follow-up 5.6 years). Results showed the lack of beneficial statins effect for atherosclerotic CVD and all-cause mortality in participants without diabetes older than 74 years. In participants with diabetes, statins showed a protective effect against atherosclerotic CVD and all-cause mortality, but this effect was substantially reduced beyond the age of 85 years and disappeared in nonagenarians. Therefore, this may affect doctors’ clinical practice in prescribing statin therapy to this group of patients.

Using PSA as a screening test for prostate cancer
There has been much publicity recently in the lay press for men to have their PSA checked with their doctor. However, evidence has been lacking this far to demonstrate that screening will reduce mortality and has been associated with overdiagnosis and overtreatment. A systematic review and meta-analysis in The BMJ looked at five randomised controlled trials with 721,718 male patients to investigate the efficacy and safety of PSA testing to screen for prostate cancer. They found that screening probably has no effect on all-cause mortality (incidence rate ratio IRR 0.99, 95% CI 0.98 to 1.01; moderate certainty) and may have no effect on prostate-specific mortality (IRR 0.96, 0.85 to 1.08; low certainty). The data corresponded to one less death from prostate cancer per 1,000 men screened over 10 years. Therefore, the authors have questioned the risks of a widespread screening programme and urges clinicians to consider the short and long-term harms to patients.

The cardiovascular risk posed by NSAIDs
The risks of diclofenac when compared to other traditional NSAIDs has never been examined in a randomised controlled trial. However, diclofenac is commonly prescribed in a number of countries and in some it is available over the counter. Concerns about risks posed makes a trial looking at risks unethical so a study group writing in The BMJ sought to examine a series of 252 nationwide cohort studies, each mimicking the strict design criteria of a clinical trial. The study included 1,370,832 diclofenac initiators, 3,878,454 ibuprofen initiators, 291,490 naproxen initiators, 764,781 healthcare seeking paracetamol initiators matched by propensity score, and 1,303,209 healthcare seeking non-initiators also matched by propensity score. The adverse event rate among diclofenac initiators increased by 50% compared with non-initiators (incidence rate ratio 1.5, 95% CI 1.4 to 1.7), 20% compared with paracetamol or ibuprofen initiators (both 1.2, 1.1 to 1.3), and 30% compared with naproxen initiators (1.3, 1.1 to 1.5). The event rate for diclofenac initiators increased for each component of the combined endpoint (1.2 (1.1 to 1.4) for atrial fibrillation/flutter, 1.6 (1.3 to 2.0) for ischaemic stroke, 1.7 (1.4 to 2.0) for heart failure, 1.9 (1.6 to 2.2) for myocardial infarction, and 1.7 (1.4 to 2.1) for cardiac death) as well as for low doses of diclofenac, compared with non-initiators. Diclofenac initiation also increased the risk of upper gastrointestinal bleeding at 30 days, by approximately 4.5-fold compared with no initiation, 2.5-fold compared with initiation of ibuprofen or paracetamol, and to a similar extent as naproxen initiation.

Management of subacute cough in primary care
Doctors working in primary care are well aware that cough is one of the most common presenting complaints for patients seeking medical advice who are invariably frustrated or anxious about underlying causes. As data was lacking on the treatment options for a subacute cough following a viral infection, a group of researchers writing in the BJGP sought to provide a systematic overview of treatment options and outcomes evaluated in randomised clinical trials. Six eligible RCTs including 724 patients were identified. These assessed montelukast, salbutamol plus ipratropium bromide, gelatine, fluticasone propionate, budesonide, and nociception opioid 1 receptor agonist and codeine. No treatment option was associated with a clear benefit on cough recovery or other patient-relevant outcomes in any of the studies or in meta-analyses for cough outcomes at 14 days and 28 days. However, reported adverse events were rather mild and reported for 14% of patients across all treatments.

Coronary CT angiography and five-year risk of myocardial infarction
Although coronary computed tomographic angiography (CTA) improves diagnostic certainty in the assessment of patients with stable chest pain, its effect on five-year clinical outcomes is unknown. Therefore, researchers performed an open-label, multicenter, parallel-group trial, published in the NEJM, in which they randomly assigned 4,146 patients with stable chest pain who had been referred to a cardiology clinic for evaluation to standard care plus CTA (2,073 patients) or to standard care alone (2,073 patients). The five-year rate of the primary end point was lower in the CTA group than in the standard-care group (2.3% vs. 3.9%; hazard ratio, 0.59; 95% CI, 0.41 to 0.84). Interestingly, more preventive therapies were initiated in patients in the CTA group (odds ratio, 1.40; 95% CI, 1.19 to 1.65), as were more antianginal therapies (odds ratio, 1.27; 95% CI, 1.05 to 1.54). The authors confirmed that the addition of CTA to those with stable chest pain provided better outcomes without higher rates of angiography or revascularisation.

High dose folic acid not protective against pre-eclampsia
Pre-eclampsia is known to be an important factor in maternal mortality affecting multiple organ systems. Epidemiological studies of the association between folic acid supplementation and the incidence of pre-eclampsia have shown a potential protective effect but finding have been inconsistent. Therefore, a randomised double blind trial in The BMJ investigated the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia in women with at least one risk factor: pre-existing hypertension, pre-pregnancy diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35. Some 2,464 pregnant women were randomised to receive either daily high dose folic acid (four 1.0 mg oral tablets) or placebo from eight weeks of gestation to the end of week 16 of gestation until delivery. Pre-eclampsia occurred in 169/1,144 (14.8%) women in the folic acid group and 156/1,157 (13.5%) in the placebo group (relative risk 1.10, 95% CI 0.90 to 1.34). There was no evidence of differences between the groups for any other adverse maternal or neonatal outcomes.

Novel lung cancer treatments 
Authors writing in the BMJ Case Reports are highlighting the effectiveness and ongoing potential of novel lung cancer therapies, specifically immunotherapy agents such as nivolumab, a T-cell programmed death 1 (PD-1) receptor inhibitor. They present a case study where a patient, who had a significant burden of disease with nodal involvement above and below the diaphragm at the time of diagnosis, was commenced on standard of care therapy: cisplatin and pemetrexed. Despite five cycles of treatment with these agents, the disease progressed significantly with the development of brain metastasis. The patient was switched to a novel immunotherapy agent, nivolumab, and had a complete response to it to the point that there was no ongoing active disease. The patient has been tolerating the treatment well with no significant adverse reactions. The authors highlight that the case demonstrate that even advanced disease with poor prognosis may be very effectively treated with novel immunotherapy agents. 

Novel prognostic model for transplant-free survival in PSC
Most prognostic models for primary sclerosing cholangitis (PSC) are based on patients referred to tertiary care and may not be applicable for the majority of patients with PSC. Researchers writing in Gut, aimed to construct and externally validate a novel, broadly applicable prognostic model for transplant-free survival in PSC, based on a large, predominantly population-based cohort using readily available variables. The derivation cohort consisted of 692 patients with PSC from the Netherlands, the validation cohort of 264 patients with PSC from the UK. Retrospectively, clinical and biochemical variables were collected and the final model included the following variables: PSC subtype, age at PSC diagnosis, albumin, platelets, aspartate aminotransferase, alkaline phosphatase and bilirubin. The C-statistic was 0.68 (95% CI 0.51 to 0.85). Calibration was satisfactory. The model was robust in the sense that the C-statistic did not change when prediction was based on biochemical variables collected at follow-up. The authors concluded the model may prove a useful tool for patient counselling, healthcare budget planning, as well as for risk stratification in clinical trials.

Author's Image

Tertius Lydgate

Originally from Northumberland, Tertius Lydgate studied medicine in Edinburgh, London and Paris. There he developed a special interest in communicable diseases and hoped to make great advances in treating and preventing them. But, after a promising start in a provincial centre of excellence in middle England, he was forced by circumstances (please, don't inquire) to abandon his high ideals. He now scrapes a living by pouring cold water on the over-enthusiastic at his private cryohydrotherapy clinic. Dreaming of the contributions he once hoped to make himself, he finds consolation in the latest medical journals and is happy to share his discoveries with his readers. He thinks that his creator, George Eliot, would have approved.
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