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Take a look at a selection of our recent media coverage:

Meta-analysis finds PCSK9 inhibitors and ezetimibe combined with statins reduce non-fatal MI and stroke in high risk patients but not death

20th May 2022

PCSK9 inhibitors and ezetimibe added to statins in high-risk cardiovascular disease patients reduces non-fatal MIs/stroke but not mortality, study shows

Adding PCSK9 inhibitors and ezetimibe to maximally tolerated statin therapy in patients at a high risk of a cardiovascular event reduces the risk of a non-fatal myocardial infarction (MI) and non-fatal stroke but does not significantly reduce either all-cause mortality or cardiovascular mortality. This was the main finding from a network meta-analysis of trials by a group of US and Chinese researchers.

The 2021 European Society of Cardiology guidelines on cardiovascular disease prevention in clinical practice recommend that a high-intensity statin is prescribed up to the highest dose that can be tolerated in order to reach the LDL target for a specific risk group. Furthermore, the joint American College of Cardiology/American Heart Association Task Force has suggested that in patients at very high cardiovascular risk and whose LDL-C level remains ≥70mg/dl (≥1.8mmol/l) on maximally tolerated statin and ezetimibe therapy, adding a PCSK9 inhibitor is a reasonable option. Previously published data has already shown that when added to statin therapy, ezetimibe produces an incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Similarly, addition of alirocumab (a PCSK9 inhibitor) to patients receiving high-intensity statin therapy, reduced the risk of recurrent ischaemic cardiovascular events

Whilst the benefits of both treatments cholesterol lowering agents are clear, the benefits to an individual patient depends upon their baseline risk. Moreover, the absolute incremental benefit derived from combining PCSK9 inhibitors and ezetimibe either separately or in combination, among individuals taking a maximally tolerated dose of statin or for those who are statin-intolerant and with different levels of baseline cardiovascular risk, remains to be determined.

For the present study, the authors performed a network meta-analysis of randomised controlled trials in which patients had a median baseline LDL cholesterol value > 1.8mmol/l and where they were randomised to receive PCSK9 inhibitors vs control, ezetimibe vs control, or PCSK9 inhibitors vs ezetimibe. The researchers assessed the relative and absolute risks (per 1000 patients treated for 5 years) in terms of non-fatal MI, non-fatal stroke, all-cause mortality and cardiovascular mortality. Patients were also categorised as being at low to very high cardiovascular risk. The authors set the minimal important difference as 12 per 1000 reductions for non-fatal MI, 10 per 10,000 for a non-fatal stroke and 8 per 1000 for all-cause or cardiovascular mortality.

PCSK9 inhibitors and ezetimibe and cardiovascular outcomes

A total of 16 trials with 111,098 patients (median age 61 years) and a median LDL cholesterol concentration of 2.71mmol/l, were followed-up for a median of 2 years and included in the analysis.

Among patients prescribed statins, addition of a PCSK9 inhibitor reduced the risk of a non-fatal MI by 19% (relative risk, RR = 0.81, 95% CI 0.76 – 0.87), non-fatal stroke by 26% (RR = 0.74) but not all-cause mortality (RR = 0.95, 95% CI 0.87 – 1.03) or cardiovascular mortality (RR = 0.95, 95% CI 0.87 – 1.03).

Similarly, the addition of ezetimibe reduced non-fatal MI and non-fatal stroke by 13% and 18% respectively but, again, there was no significant effect on all-cause or cardiovascular mortality.

Among adults with a very high cardiovascular risk, the authors calculated that adding a PCSK9 inhibitor to statins would lead to 16 fewer non-fatal MIs and 21 non-fatal strokes. Adding ezetimibe to a similar or equivalent statin patient, would lead to 14 fewer non-fatal strokes and 11 fewer MIs. Finally, adding PCSK9 inhibitors and ezetimibe to a statin would reduce non fatal strokes by 14 per 1000 and stroke by 17 per 1000, although there was no impact on all-cause or cardiovascular mortality.

The authors also found that among patients with low to moderate risk of cardiovascular disease, adding either a PCSK9 inhibitor provided no additional benefit over statin therapy alone. In other words, it was only patients with the highest cardiovascular risk who benefited from adding either ezetimibe or a PCSK9 inhibitor to their statin. Similar reductions, again only among high or very high risk individuals and a lack of mortality benefit, were observed in patients intolerant of statins.

The authors concluded that the benefits of adding PCSK9 inhibitors and ezetimibe were limited largely to patients only with a high or very high cardiovascular risk.

Citation
Khan SU et al. PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis BMJ 2022

DOACs superior to prophylactic doses of heparins for thromboprophylaxis in non-cardiac surgery

17th March 2022

DOACs seem more effective than low molecular weight heparins for the prevention of symptomatic venous thromboembolism in non-cardiac surgery

Direct acting oral anticoagulants (DOACs) are more effective for the prevention of symptomatic venous thromboembolism in comparison to prophylactic dosing with low molecular weight (LMW) heparins. However, DOCAs are no more effective than high dose LMW heparins in non-cardiac surgical patients. This was the conclusion of a systemic review and network meta-analysis by researchers from the Department of Health Research Methods, Evidence, and Impact, McMaster University, Ontario, Canada

A venous thromboembolism is a significant problem in the peri-operative period with the potential to increase patient morbidity, mortality and associated health care costs. Typically, a venous thromboembolism presents as either a deep vein thrombosis or a pulmonary embolism. Although both the DOACs and LMW heparins are recognised as convenient and effective prophylaxis regimens against venous thromboembolism for at-risk surgical patients, there is a lack of direct and comparative evidence to guide clinician’s choice. Nevertheless, it seems that in practice, one survey of thrombosis experts revealed how 85.9% would recommend the use of LMW heparins.

With a level of uncertainty over the relative benefits of either DOACs or LMW heparins, the Canadian team undertook a systematic review and network meta-analysis of existing randomised controlled trials in which there was a comparison of LMW heparins, DOACs and no active treatment for thromboprophylaxis in patients undergoing non-cardiac surgery. The researchers suspected that the relative efficacy of the two therapeutic options would be similar across a range of surgical settings and hence used a network meta-analysis to enable a comparison to be made where there was an absence of direct comparative studies.

The team included randomised trials in adult patients (> 18 years of age) undergoing non-cardiac surgery, including general, urological, gynaecological, orthopaedic and thoracic procedures. They searched for studies in which the use of low dose LMW heparins (e.g., enoxaparin 40 mg daily), high dose (e.g., enoxaparin 30 mg twice daily) and DOACs had been employed. The outcome of interest was a reduction in symptomatic pulmonary embolism and/or deep vein thrombosis and they considered major bleeding as the primary anticipated harm.

DOACs and symptomatic venous thromboembolism

A total of 68 eligible studies with 45,445 patients were included in the analysis. In 25 trials with 30, 230 patients, 0.78% had a symptomatic venous thromboembolism and in 61 studies, 0.25% had a pulmonary embolism.

Overall and compared to no treatment, all three interventions were associated with a significant reduction in the odds of symptomatic venous thromboembolism. For example, DOACs (OR = 0.17, 95% CI 0.07 – 0.41), LMW heparins (OR = 0.33) and high dose LMW heparins (OR = 0.19).

When the different treatments were compared in the network meta-analysis, the use of DOACs was associated with a significant reduction in symptomatic venous thromboembolism compared to LMW heparin (odds ratio, OR = 0.53, 95% CI 0.32 – 0.89, p = 0.02). However, there was no significant difference compared to high dose LMH heparin (OR = 0.93, 95% CI 0.51 – 1.71).

In terms of bleeding, both DOACs and both doses of LMW heparins were associated with an increased risk of a major bleed. The risk was approximately two-fold higher for both DOACs and LMW heparins (e.g., OR = 2.01 for DOACs).

The authors concluded that both DOACs and LMW heparins are effective for symptomatic venous thromboembolism in non-cardiac surgery and that the former class of drugs are probably more effective and LMW heparins when used at the standard prophylactic dose.

Citation
Marcucci M et al. Benefits and harms of direct oral anticoagulation and low molecular weight heparin for thromboprophylaxis in patients undergoing non-cardiac surgery: systematic review and network meta-analysis of randomised trials BMJ 2022