The American College of Cardiology 2018; a Starbuckian ODYSSEY and a Black Barbershop

Matt Daniels is currently a Wellcome Trust Intermediate Fellow (WT098519MA) and Honorary Consultant Cardiologist in the Cardiovascular Medicine Department at Oxford University and a specially appointed visiting Professor in the University of Osaka, Japan. In Oxford, he leads the Stem cell-derived models of inherited heart disease group making novel in vitro disease models and phenotyping tools based on light emitting proteins and microscopy. His clinical practice includes clinical trials of medical devices, digital health platforms and novel therapeutics. He is an expert in Inherited Cardiac Conditions, percutaneous structural interventions and congenital heart disease. He is a member of the British Cardiac Society, the American Heart Association, Society of Cardiac Angiography and Interventions, as well editorial board member of Expert Reviews in Molecular Medicine. He is a member of the BHF Regenerative Medicine Initiative, the Cardiovascular Genomics England Clinical Interpretation Panel and the Emerging Leaders Mentor program established by SCAI who supported his attendance at ACC18. He is social media director for the CSI foundation meetings. Twitter @hiPS_cm_lab.

If you have not been to the ACC Scientific Sessions, you might not realize this meeting is a lot closer to the clinical coalface than it is to basic science. That is not a bad thing, but the reality is that cardiovascular research is slovenly in comparison to the inroads basic science has made in the other major disease of our era, cancer. We are tied down with descriptive disease entities like ‘atrial fibrillation’ (AF).

AF is common, you have a lifetime risk of 1:4 of developing it.¹ Contemporary AF classification describes how long it lasts (paroxysmal, persistent or permanent) rather than what causes it. It’s like talking about cancer in terms of the amount of tumour – a Starbuckian classification of Tall, Grande and Venti which oncology abandoned decades ago. AF causes stroke, and death by promoting clot formation in the heart,¹ so there was good news on the clinical horizon that the anti-coagulants (that reduce stroke and death in patients with AF) based on factor Xa inhibition now appear to have an effective antidote² that translates into clinical practice based on the interim analyses presented for the Annexa-4 study (http://www.acc.org/latest-in-cardiology/articles/2018/03/07/15/53/mon-1045am-annexa-4-andexanet-for-reversal-of-anticoagulation-in-factor-xa-acc-2018). This should be good news for the 100 000 patients experiencing a major bleed in North America every year because of their blood thinner.

The challenge of turning basic science into real world clinical treatments like this cannot be underestimated. A few of the late breaking trials in ACC18 highlight this.

Hot on the heels of the FOURIER trial (presented in the same meeting in 2017) which looked at the role of evolocumab in patients with stable angina³ and emerged to mixed reviews, the randomized double-blind ODYSSEY trial reported its results (http://www.acc.org/latest-in-cardiology/clinical-trials/2018/03/09/08/02/odyssey-outcomes). ODYSSEY evaluated a different PCSK9 neutralizing monoclonal antibody to mimic one of the greatest successes of Mendelian randomization⁴ to reduce serum low density lipoprotein (LDL) cholesterol in recently revascularized patients who were well medicated and on maximal doses of super-statin. Patients receiving alirocumab saw their LDL fall like a stone (>50%) in days. By the time of an average follow-up of nearly 3 years, this translated into a 16% relative risk reduction in the primary endpoint (death, heart attack, etc). The interesting thing for me was that although huge falls in LDL were seen early in the trial, the endpoints only started to separate well after a year. This appears to be at odds with earlier trials like PROVE-IT,⁵ which compared a low potency to a high potency statin regime. Here early changes in LDL cholesterol translated into early reduction in clinical endpoints. Finding a biologically plausible mechanism to explain this might be as easy as finding the funds to pay for something that falls into medicines most expensive class of treatments and delivers an absolute risk reduction of just over 1.5% per year.

Financial barriers are not the only obstacles to clinical success. Hypertension accelerates atherosclerotic diseases processes that ultimately cause heart attack, stroke and death.⁶ There are more ways to try and reduce blood pressure pharmacologically than there are flavours of chewing gum, but delivering benefits to all eligible patient populations in the developed and developing world is incomplete. One argument might be that the underlying vascular biology – the subject of the current Spotlight Issue of Cardiovascular Research⁷ – can be influenced by ethnicity and gender. Therefore, tablets working on one side of the world might not necessarily work as well on the other. Another argument would be that the care model to deliver the medication is culturally sensitive and some communities don’t engage with the white middle class model of primary care that normally delivers and monitors these medications.

Male African-Americans have been a very difficult group to target with anti-hypertensive therapy in well-resourced healthcare environments. In easily the most important piece of work presented at ACC18 the ‘Black Barbershop’ study took clinical trial design to another level.⁸ A small number of hypertensive patrons (n = 319) in a small number of Californian barbershops (n = 52) became patients and trial participants leading to randomization to standard care or pharmacist directed medication introduction and monitoring in the barbershop itself. The average male in this study gets his hair cut every other week and has maintained this bond with his barber for a decade. That strong social connection was essential in unlocking a previously well-bolted door and over the course of 6 months a vast gulf appeared between the standard care model and this one. It costs billions to find and get a new drug like alirocumab to the market. But, even if successful in trials, these never reach patients who won’t take tablets or visit their doctor. Simple studies like,⁸ and the recently conducted, ORBITA⁹ expose the lacunes in contemporary trial design, which leave unpalatable blindspots in the clinical conscience. Hopefully we are now witnessing an era where these gaps can be plugged.

So where is the next horizon? The potential for pharmacogenomics to guide personalized medicine seems to be a safe bet. The problem is that it has been a safe bet for a long time with very few examples of practical relevance. This strategy requires two treatment options for a given genotype so that a genuine treatment option is realized. Having highlighted the difficulty of BP control which targets everyone, what are the additional challenges to this model of care? Surprisingly cardiology might jump the que and expose these.

If I put a stent in your coronary artery for any reason I would also give you an asprin and another type of antiplatelet agent to try and stop a thrombus forming within the freshly deposited metal scaffold.¹⁰ Unfortunately, in-stent-thrombosis has a significant mortality. The most common choice for the second agent is clopidogrel, a prodrug that needs to be activated by an enzyme normally found in the liver. Particular genotypes do a bad job of this.¹¹ Alternatives to clopidogrel (which tend to be more expensive) are now available, so it appears reasonable to ask the question ‘can genetic testing run alongside coronary stenting and influence discharge medication?’

This would prevent patients receiving tablets they might not benefit from while protecting the healthcare budget from high cost options. There is only one thing in the way. The interventional cardiologist who, lets be honest, was probably not the one paying most attention to the hepatic drug metabolism lecture at clinical school. This problem was tackled in a couple of studies PHARMCLO¹² and ADAPT-PCI (http://www.acc.org/education-and-meetings/image-and-slide-gallery/media-detail? id=8E62E15C948B4AE0BB63DAB0747D9F3F) and indeed in spite of the genotype data, and the availability of alternatives overcoming the inertia in prescribing practice was encountered. So even if we can do the genetics, and have the treatment options, successful clinical implementation will not necessarily follow.

Finally, I will highlight the Simon Dack Keynote lecture from Prof Nanette Wenger (Emory University) who gave a very powerful summary of a careers work to overturn the knowledge vacuum that developed in women’s cardiovascular health.¹³ Since what we do in the clinical arena is fuelled by what comes out of basic science we cannot continue to ignore gender differences in basic science¹⁴ and accept small animal studies that use exclusively male animals in their experimental arms in order to preserve the female animals needed for breeding. This lecture highlighted that since the 114th US Congress (2015–16) there is a legislative requirement¹⁵ for equal numbers of female cells and animals in basic research – does this happen in your lab?

In summary, incremental gains in the clinical domain are often premised around basic science discoveries that now must include all the populations that may benefit.^14,15 Even when the underpinning science is solid, e.g. Ref. 4, developing effective therapy^3,5 by itself may not be enough if the payers do not have the appetite for the bill, or if the patients don’t engage with the way it is delivered and monitored.⁸ Inertia among clinicians should be anticipated when new concepts, particularly from unrelated disciplines are introduced.¹² A major challenge for basic scientists therefore is to scope out opportunities arising as treatment strategies struggle to make the successful transition to practical use. For this to happen, basic scientists need to keep pace with clinical outcomes or we risk two fields divorcing after the initial translation phase, which may not be successful, begins. Funders in this space need to resist the temptation continually invest in new theories and maintain interest in testing old ones where considerable untapped benefit may remain.

Funding

Wellcome Trust, WT098519MA.

Conflict of interest: none declared.