Alex Nowbar’s research reviews—12 November 2018

Alex Nowbar reviews the latest research from the top medical journals

The indispensable inhalers: Triple therapy for COPD
Zheng et al’s elegant meta-analysis of 21 randomised controlled trials reveals a lower rate of moderate or severe exacerbations of COPD with long acting muscarinic antagonist (LAMA) plus long acting β agonist (LABA) and inhaled corticosteroid (ICS) compared to using one or two of the three therapies. Health related quality of life and lung function were also better and adverse events weren’t worse. However, the link between triple therapy and increased risk of pneumonia lurked in the comparison of triple therapy with LAMA + LABA. Still the evidence points towards triple therapy being effective and safe overall. Even if 80% of the trials were industry funded.

The shifting sands: Extra low P values
I’ll start with my disclosures. I like low P values and I cannot lie. You other fellows can’t deny. But Wayant et al studied the potential impact of lowering the threshold for statistical significance from 0.05 to 0.005. They analysed the primary endpoints of randomised controlled trials in three high impact factor journals in 2017, and found that 70.7% of the statistically significant primary endpoints would have remained significant based on a 0.005 threshold. These our fascinating data, but our community may be some way away from referring to P values between 0.005 and 0.05 as “suggestive.”

A noble neutral: Nitrite for heart failure with preserved ejection fraction
The INDIE-HFpEF trial randomised patients to three times a day inhaled sodium nitrite or placebo to see if it would improve exercise capacity in patients with heart failure with preserved ejection fraction. The double blind crossover trial design seems flawless. Despite promise from preliminary work prior to this trial, there was no significant difference between groups. Heart failure with preserved ejection fraction remains an enigma.

An HIV horoscope: Dolutegravir based dual antiretroviral therapy
Antiretroviral drugs have many adverse effects. This gets amplified by the long durations of treatment they are intended for. The double blind randomised controlled trials, GEMINI-1 and 2, found dual therapy with dolutegravir and lamivudine to be non-inferior to dolutegravir plus tenofovir and emtricitabine for a primary endpoint of HIV viral load at 48 weeks. These data show another promising dual therapy option (there are already other trials of dual therapies for HIV). But what this means for future care is unclear. Is enough known about the long term impact of this option to start using it safely? Will resistance develop?

The powerful paglaflozins: Meta-analysis of SGLT2 inhibitors for cardiovascular outcomes
This meta-analysis of three large randomised controlled trials confirms the benefit of sodium-glucose cotransporter-2 (SGLT2) inhibitors in reducing hospitalisations for heart failure in patients with type 2 diabetes. Interestingly, this benefit was seen in patients with and without a history of heart failure. For a moment, I’ll consider something other than hearts though. Developed for use in those with type 2 diabetes, these drugs also reduced the risk of progression of renal disease. So for patients with type 2 diabetes, all roads seem to lead to a SGLT2 inhibitor—especially if they already have established cardiovascular disease.

A withdrawal warning: Treatment after recovery from dilated cardiomyopathy
The TRED-HF study is a pragmatic open label pilot trial that randomised patients with dilated cardiomyopathy who were now asymptomatic to phased treatment withdrawal versus continued treatment. Forty four per cent of patients who had treatment withdrawal relapsed while no patients relapsed in the continued treatment group. The definition of relapse included N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements, imaging markers (by MRI), or clinical signs and symptoms. In this study most of the relapses were of the BNP or imaging deterioration variety, rather than clinical. These data suggest that the resolution of cardiac function impairment may not necessarily represent recovery from dilated cardiomyopathy. This type of research is highly commendable as it can provide the data needed to accurately inform patients of the risks of coming off medications if they wish to do so. The impact of this work could have been even greater if it was double blinded.

Annals of Internal Medicine
A queer question: Troponin for stable coronary artery disease
The study question for Hammadah et al was whether high sensitivity troponin could be useful for excluding inducible myocardial ischaemia in patients with known coronary artery disease. The apparent rationale for the study was the overuse of stress testing. They found inducible ischaemia and cardiovascular events to be unlikely with a very low troponin result. These data are interesting, but I’m not sure that the right question was asked in the context of a mostly asymptomatic population of people with known coronary artery disease. I question whether finding ischaemia in this group of patients has a meaningful impact on their management. Perhaps the implication is that those with inducible ischaemia should get invasive angiograms and be considered for revascularisation, but this has no evidence of prognostic benefit so why do any such test in asymptomatic people?

A pretty penny: Alirocumab after acute coronary syndrome
Alirocumab is one of the much hyped PCSK-9 inhibitors intended to reduce cardiovascular risk. Based on the British National Formulary, it is over 100 times more expensive than high dose atorvastatin. But it appeared to do a good job in a large double blind randomised controlled trial, ODYSSEY OUTCOMES, with a hazard ratio of 0.85 (CI 0.78 to 0.93) for its primary endpoint of cardiovascular death, myocardial infarction, stroke, and hospitalisation for unstable angina. The patients had had acute coronary syndrome within the past year, had high cholesterol that was not likely to come down with tablets and diet management, and were already on high intensity or maximum tolerated statin therapy. People whose cholesterol isn’t likely to come down are sometimes people with very high cholesterol or non-responders to treatment, but I suspect that some met these criteria by being non-adherent. It is possible that simply by having fancy packaging (being injectable and expensive and general marketing), alirocumab therapy achieves better adherence to a form of lipid lowering. It is unknown whether much cheaper lipid lowering therapies would have been just as effective at ensuring compliance in this patient group if they were also packaged prettily. Hopefully, there will be some non-pharma sponsored analysis before widespread use in patients.

An inflammation initiative: Methotrexate after MI or multivessel coronary disease
There is a hypothesis that inflammation begets atherosclerosis. The CIRT investigators tested methotrexate (for inhibition of inflammation) for secondary prevention of cardiovascular disease, but unfortunately there was no benefit even when they expanded the primary endpoint to include hospitalisation for unstable angina that led to urgent revascularisation (the aim being to have more events and therefore needing to enrol fewer patients to show a difference). Before the change in primary endpoint had been fully implemented, the trial was stopped early for futility. The golden bullet for cardiovascular prevention is far from close.

A fishy future: Icosapent ethyl on top of statin therapy for people with high triglycerides
Now here’s a really low P value. The pharma sponsored REDUCE-IT trial is a double blind randomised controlled trial of icosapent ethyl versus placebo in over 8000 patients with high triglycerides and either cardiovascular disease or high cardiovascular risk. The primary endpoint (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularisation, or unstable angina) was met with a mega low hazard ratio of 0.75. The P value shown at the American Heart Association conference was 0.00000001. I hope that the game changer here wasn’t just the unusual choice of placebo, which might have resulted in more events thereby weighting the trial in favour of the new therapy. They used “a placebo that contains mineral oil to mimic the color and consistency of icosapent ethyl.” What do we know about mineral oil? I would argue not enough to be using it as the control for a large practice changing trial. But the US FDA approved it so that makes it OK. Even so, this trial is pretty convincingly positive. There seemed to be some extra hospitalisations for atrial fibrillation and serious bleeding adverse events for your money though.

A sorry supplement: Marine N-3 fatty acids for prevention of cardiovascular disease and cancer
The non-pharma funded VITAL trial compared n-3 fatty acids with placebo in a double blind randomised controlled trial. The primary endpoint was a composite of myocardial infarction, stroke, cardiovascular death, and invasive cancer. The hazard ratios were 0.92 for the cardiovascular endpoint and 1.03 for the cancer endpoint and were not statistically significant. A stark contrast to the supplement tested in the REDUCE-IT.

A PIONEER-HF promise: Sacubitril–valsartan in decompensated heart failure
You may have noticed a slight cardiovascular hue to the journals this week. The double blind PIONEER-HF trial, complete with classic cardiology acronym, tops it off. It randomised over 800 patients with acute decompensated heart failure to sacubitril-valsartan or enalapril. Sacubitril is a neprilysin inhibitor. Neprilysin is an enzyme that breaks down B-type natriuretic peptide. The sacubitril-valsartan combination has previously been tested in a different group of patients: ambulatory outpatients. In this trial, the medication was carefully initiated in inpatients. The primary endpoint was a change in N-terminal pro-B-type natriuretic peptide concentrations (NT-proBNP). There was a much greater reduction in the NT-proBNP concentration with sacubitril-valsartan compared to enalapril, with a similar safety profile. I am surprised by this choice of non-clinical primary endpoint, but they did find fewer patients had hospitalisation for heart failure with sacubitril-valsartan.

A textbook trial: Phase 2 for new gonorrhoea antibiotic
This non-pharma funded US randomised controlled trial of zoliflodacin for urogenital gonorrhoea infection showed high microbiological cure rates. It wasn’t as good as the control (ceftriaxone) for pharyngeal infection, especially when using a lower dose, but was otherwise promising (for rectal and urogenital disease) with no alarming safety signals. It was not blinded. Watch this space, I suppose.

The unfortunately unsuccessful: Sildenafil for idiopathic pulmonary fibrosis
Sildenafil, which is used as a treatment for pulmonary hypertension, had shown a mildly promising signal for benefit in idiopathic pulmonary fibrosis in a previous trial so was tested in this double blind trial as an add-on to nintedanib in patients with severely impaired gas exchange. Two hundred and seventy four patients were randomised to nintedanib plus sildenafil or to nintedanib only, but there was no benefit in the respiratory questionnaire in terms of breathlessness or health related quality of life. A well conducted trial and well written paper though.

An infection improvement: Point prevalence survey of healthcare associated infections
This US study of 199 hospitals contains good news. In 2015, the prevalence of healthcare associated infections was lower than in 2011 (3.2% versus 4% p<0.001). The reduction appeared to be driven by fewer surgical-site infections and urinary tract infections.This is excellent progress. However, the prevalence of pneumonia and clostridium difficile did not decrease. These data are a reminder of the importance of continuing to look inwards (doing better at things we know, like aseptic technique) as well as looking outwards (for new therapies etc).

Alex Nowbar is a clinical research fellow at Imperial College London.

Competing interests: None declared