Oral isotretinoin confirmed as most effective treatment for acne in network meta-analysis

27th July 2023

A network meta-analysis of 221 randomised controlled trials with over 65,000 patients, has confirmed that oral isotretinoin is the most effective acne treatment.

Acne is extremely common, affecting virtually everyone between the ages of 15 and 17 years to some extent, but is moderate to severe in up to 20% of cases. Acne can be managed with broad range of topical and oral agents including antibiotics and even aldosterone receptor antagonists such as spironolactone.

Now, in the largest network meta-analysis into pharmacological interventions in acne vulgaris to date, published in the Annals of Family Medicine, researchers from Taiwan and the US concluded that oral isotretinoin is the most effective treatment.

The team sought to provide broad and detailed comparative efficacy data for a range of pharmacological interventions in acne to reduce both inflammatory and noninflammatory lesions. The primary outcome of interest was the mean percentage reduction in total, inflammatory, and noninflammatory lesions, and the mean absolute reduction in lesion counts were secondary outcomes.

Oral isotretinoin and reduction in lesion count

The analysis included a total of 210 articles describing 221 trials, which enrolled a total of 65,601 patients. Across all of the trials, the mean age of patients was 20 years and the median duration of treatment was 12 weeks. In addition, the median baseline lesion counts were 71.5 for the total lesions, 27 for inflammatory lesions and 44 for noninflammatory lesions.

The comprehensive analysis compared 37 treatment nodes, which included six oral antibiotics, five topical antibiotics, oral isotretinoin, five topical retinoids, six combined oral contraceptives, topical clascoterone, 10 combination therapies, benzoyl peroxide (BPO), azelaic acid and placebo.

The most effective treatment, compared to placebo, was oral isotretinoin (mean difference, MD = 48.41, p = 1.0). The second most effective option was triple therapy containing a topical antibiotic, a topical retinoid and BPO (MD = 38.15, p = 0.95). This was followed closely by triple therapy with an oral antibiotic, a topical retinoid and BPO (MD = 34.83, p = 0.90).

The researchers also found a similar ranking of treatment efficacy in the analysis of absolute reduction in total lesion count.

When examining mono-therapies, both oral and topical antibiotics had comparable efficacy to topical retinoids for inflammatory lesions. In contrast, oral or topical antibiotic therapy was far less effective for noninflammatory lesions and the researchers advised against monotherapy due to the risk of developing bacterial resistance.

Another comparison revealed how the combination of a topical retinoid and BPO was as effective as a combination of an oral antibiotic with a topical retinoid at reducing inflammatory lesion counts.

Early emollient use among high-risk infants prevents atopic eczema

12th January 2023

An analysis suggests that early emollient use prevents the development of atopic eczema in high-risk infants especially if an emulsion is used

Early prophylactic emollient use (EU) among high-risk infants, prevents the development of atopic eczema (AE) and emollient emulsions are likely to be the most effective, according to the findings of a network meta-analysis by Chinese researchers.

Atopic eczema is a chronic, inflammatory disorder of the skin and which affects between 0.9% and 22.5% of children aged 6 to 7. It is characterised by a persistent skin dryness, erythema and pruritus, leading to an impaired in quality of life. While the precise cause remains to be determined, a feature of the disease is a defective epidermal barrier that enables greater water loss through the skin leading to dryness.

However, this can be remedied to a large extent through EU, which alleviates the clinical symptoms and reduces the need for anti-inflammatory agents such as topical corticosteroids. In recent years, it has been suggested that early emollient use to high-risk infants, i.e., those with a family history of the disease or other atopic conditions such as asthma or hay fever, might prevent the subsequent development of AE.

The evidence to support this is equivocal, with one meta-analysis finding that use of emollients made no difference, whereas another concluded that prophylactic emollient use, initiated in early infancy may prevent AE, especially in high-risk populations and when used continuously. A further consideration and which might account for the observed discrepancies in the meta-analyses, is the type of emollient used. In fact, there is some data to show that different emollient creams have different effects on the skin and only certain types have the ability to improve the skin’s barrier and protect against irritants that trigger eczema.

With some uncertainty over whether early EU could prevent the development of AE, in the present study, the Chinese researchers undertook a network meta-analysis to address both whether the early application of emollients in infancy could prevent the later development of AE and which types of emollients were most effective. They used the surface under the cumulative ranking area curve (SUCRA) which to rank the different types of emollients, which could be either emulsions, creams or mixed formulations (e.g., creams, gels) and where a higher SUCRA value indicated a greater preventive efficacy. 

Early emollient use and the development of atopic eczema

A total of 11 trials with 3,483 subjects were included in the network meta-analysis. Overall, the results showed that the development of AE was significantly lower after early emollient application (Risk Ratio, RR = 0.75, 95% CI 0.57 – 0.99, p = 0.001). In addition, this risk was also significantly lower, when the analysis was restricted to high-risk infants (RR = 0.64, 95% CI 0.47 – 0.88).

When examining the different types of emollients, the SUCRA values were highest for emollient emulsions, with values of 82.6% for all populations and 78.0% for high-risk populations.

The authors concluded that the early application of emollients is an effective strategy for preventing AE development in high-risk infants and that an emollient emulsion may be the optimal type of formulation.

Citation
Liang J et al. Systematic review and network meta-analysis of different types of emollient for the prevention of atopic dermatitis in infants. J Eur Acad Dermatol Venereol 2022

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