Seth Martin, MD, MHS

Dr. Martin is an assistant professor at the Ciccarone Center for the Prevention of Heart Disease at the Johns Hopkins University School of Medicine.

	In the opening Late Breaking Clinical Trial session at the AHA Scientific Sessions 2017 in Anaheim, we were treated to the results of the PRESERVE (Prevention of Serious Adverse Events Following Angiography) trial, presented by Dr. Steven Weisbord of VA Pittsburgh Healthcare System. This trial leveraged a factorial design to answer two questions of longstanding clinical interest in patients undergoing angiography and at high risk for renal complications from contrast exposure.

	First, does intravenous sodium bicarbonate offer clinical benefit over intravenous sodium chloride, and second, is oral acetylcysteine more efficacious than placebo? The trial was funded by the U.S. Department of Veterans Affairs Office of Research and Development and the National Health and Medical Research Council of Australia, and along with the AHA podium presentation the

	The background here is that students, residents, and fellows have long been trained to administer IV sodium bicarbonate and oral acetylcysteine as renal prophylaxis to patients undergoing angiography. Mechanistically, it has been postulated that urinary alkalinization and scavenging of reactive oxygen species could protect the renal tubular epithelial cells from injury with exposure to iodinated contrast. The practice of periprocedural IV sodium bicarbonate and oral acetylcysteine has been widely adopted and is deeply engrained despite a lack of definitive evidence for efficacy. Small scale evidence has suggested benefit but up until PRESERVE efficacy was not adequately evaluated.

	In a 2-by-2 factorial design, PRESERVE randomized 5,177 patients scheduled for angiography and at high risk for renal complications to IV 1.26% sodium bicarbonate vs IV 0.9% sodium chloride, and oral acetylcysteine for 4 days vs oral placebo. The primary outcome was a composite of death, need for dialysis, or a persistent increase ≥ 50% from baseline in serum creatinine at 90 days. A secondary outcome was contrast-associated acute kidney injury.

	Participants were recruited most commonly from VA medical centers in the United States, as well as from medical institutions in Australia, Malaysia, and New Zealand. Risk of renal complications was based on reduced eGFR:  15-44.9 mL/min/1.73 m

	The PRESERVE trial was stopped early after a prespecified interim analysis showed no effect of sodium bicarbonate and acetylcysteine on the primary outcome. It occurred in 4.4% of patients in the sodium bicarbonate group and 4.7% in the sodium chloride group (OR 0.93; 95% CI 0.72 to 1.22; P=0.62). Similarly, the primary outcome occurred in 4.6% of those in the acetylcysteine group versus 4.5% of placebo allocated participants (OR 1.02; 95% CI 0.78 to 1.33; P=0.88). Episodes of contrast-associated acute kidney injury were also similar in frequency in each of the groups.

	Therefore, in this large trial involving approximately five thousand high risk angiography patients, there was a strongly null result for clinical benefit of IV sodium bicarbonate vs IV sodium chloride, or for oral acetylcysteine vs placebo. PRESERVE, as the largest trial of its kind, provides convincing and, theoretically, practice-changing results.

	On a practical level for patients, they don’t need to bother with oral acetylcysteine. On a practical level for hospitals, the PRESERVE results simplify the supply chain for IV fluids, as noted by Dr. Núria Pastor-Soler, a nephrologist at the University of Southern California in Los Angeles. Sodium chloride is readily available whereas sodium bicarbonate requires on-site preparation.

	But such behavioral shifts don’t happen quickly, particularly when clinical practices are deeply entrenched, and, in this case, written into resident survival guides. We can expect it to take some time for even these indisputable trial results to diffuse into practice.

 Steven D. Weisbord SD, Gallagher M, Jneid H, et al for the PRESERVE Trial Group. Outcomes after angiography with sodium bicarbonate and acetylcysteine. N Engl J Med. November 12, 2017. DOI: 

Articles

Results of the large trial, unveiled at AHA 2017, appear indisputable, but will prophylaxis with sodium bicarb and acetylcysteine yield ground?

Will PRESERVE Trial Results Shift Practice in Renal Prophylaxis?

“Disinformation” on statins is prevalent and has contributed to these medicines being underutilized in prevention of cardiovascular disease.

	This short slide show presents 5 common myths about the effects of statin drugs followed by evidence from large scale trials to debunk them.

	We are fortunate to have clear and convincing evidence on statin effects. As noted by Dr. Collins during his presentation, erroneous information on statins taken as fact can lead to death and disability.

	Today there is a need for rapid, robust, and trusted rebuttal of disinformation that is relevant to public health.

 Statins cause side effects in 20% of patients. 

Discontinuation of statins in routine care settings: a cohort study.

 2013;158:526-34. doi: 10.7326/0003-4819-158-7-201304020-00004.

Statins commonly cause awful muscle problems.

Interpretation of the evidence for the efficacy and safety of statin therapy.

 2016; 388: 2532–61.http://dx.doi.org/10.1016/

 Statins and low cholesterol cause cancer.

: Cholesterol Treatment Trialists' (CTT) Collaboration.

Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy.

2012;7:e29849. doi:  10.1371/journal.pone.0029849

 Statins commonly cause diabetes without prior notice.

Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. 

Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial

 Most statin trials exclude patients during a run-in phase who would otherwise suffer from statin
	side-effects.

A systematic review of statin-induced muscle problems in clinical trials.

 Am Heart J. 2014;168:6-15. doi: 10.1016/j.ahj.2014.03.019.

At AHA.17, Dr Rory Collins offered large-scale trial data to help dispel dangerous disinformation still circulating about the effects of statins. 

5 Stubborn Statin Myths vs Data that Refute Them

 on management of hypertension in adults, developed by the American College of Cardiology and American Heart Association, in collaboration with 9 other professional organizations, offer clinicians and patients alike an opportunity to help reduce the incidence, prevalance and public health impact of high blood pressure (BP) in the United States.

	This short slide show provides a simple illustration of the revised guidelines' key principles: accurate BP measurement, a new BP classification system, a lower BP target value, a renewed emphasis on lifestyle modification during treatment, and incorporation of underlying cardiovascular risk into decisions on pharmacotherpay.

	Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 

	Muntner P, Carey RM, Gidding S, et al. Potential US population impact of the 2017 American College of Cardiology/American Heart Association High Blood Pressure Guideline. 

Click through this short case study for an illustration of the key principles put forth in the revised ACC/AHA guidelines on hypertension diagnosis and management. 

2017 ACC/AHA Hypertension Guidelines: Case Study

	The potential for artificial intelligence (AI) to revolutionize how medicine is practiced presents as a double-edged sword-that was one of the take-aways from back-to-back sessions presented by cardiologists Geoff Tison, MD, assistant professor of medicine in the division of cardiology from the University of California San Francisco and Partho Sengupta, MD, professor of medicine and director of interventional echocardiography and cardiac ultrasound research and core lab at the Mount Sinai Hospital in New York at the Health Tech Summit during the American Heart Association Scientific Sessions in Anaheim last week.  

	On one hand, machine learning could help re-engineer the workflows that now render so many physicians and other healthcare professionals critically overworked and overextended. On the other hand the algorithms that mimic human cognitive functions like learning and problem solving, are data hungry, have labeling problems, and can leave us wondering how exactly a particular solution was derived in that “black box” to which we have no access.

	Drs Tison and Sengupta also reminded their audiences that scientists still control the quality of the information that serves as the substrate for automated neural processing and that the “garbage in, garbage out” rule of data processing still holds true.

	With those caveats on board both physicians discussed real-world applications of AI, including Dr Sengupta’s presentation on AI used to automate morphologic and functional assessments in echocardiology. A specific example was use of AI to help better understand hypertrophic cardiomyopathy in athletes.

	Dr Seth Martin, assistant professor at the Ciccarone Center for the Prevention of Heart Disease at the Johns Hopkins University School of Medicine, highlights the two presentations in this short podcast.

Podcasts

Two cardiologists respected for their technological expertise took the concept of AI from blue sky to concrete clinical examples at AHA 2017.

Cardiologists Talk Concrete Application of Artificial Intelligence

Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 

Muntner P, Carey RM, Gidding S, et al. Potential US population impact of the 2017 American College of Cardiology/American Heart Association High Blood Pressure Guideline. 

A shift to earlier intervention and emphasis on basics like proper BP measurement and intensive lifestyle change are the key revisions.

New 2017 ACC/AHA Hypertension Guidelines, At-a-Glance

	In a standing-room-only Late Breaking Clinical Trial session at the American Heart Association Scientific Sessions, Marc P. Bonaca, MD, MPH, of the TIMI Study Group at Brigham and Women’s Hospital, shared the results of a substudy that examined patients with peripheral arterial disease (PAD) enrolled in the FOURIER (Further Cardiovascular OUtcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial. The response in these patients to LDL-C lowering with evolocumab and related clinical outcomes were truly impressive. I found the positive results an interesting juxtaposition to the session that I’d attended earlier in the day on barriers to access for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

	FOURIER was a landmark randomized controlled trial of evolocumab versus placebo on top of maximal statin therapy in 27,564 patients with atherosclerotic cardiovascular disease (ASCVD). At baseline, participants were considered to have PAD if they had intermittent claudication plus an ankle brachial index of <0.85, or alternatively if they had undergone a peripheral vascular procedure. With a median follow-up of 2.2 years, patients were followed for the primary composite endpoint of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization. A key secondary composite endpoint was cardiovascular death, MI, or stroke. Major adverse limb events (MALE) were also recorded, defined as acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia.

	Among the 3,642 patients with PAD in FOURIER, evolocumab conferred a significant 21% relative reduction for the primary cardiovascular endpoint and 27% relative reduction in the secondary cardiovascular endpoint. There was no significant heterogeneity in treatment effect compared with patients who did not have PAD, and because they had a higher absolute risk for events, the PAD patients exhibited a higher absolute risk reduction of 3.5% (number needed to treat, 29) compared to other patients.

	The clinical benefit of evolocumab in PAD patients extended beyond major adverse cardiac events (MACE) to MALE where there was a 42% relative risk reduction. There was even a consistent reduction in MALE in patients without PAD, and the relationship between lower achieved LDL-C and lower risk of limb events extended to LDL-C levels as low as <10 mg/dL. Of note, FOURIER confirmed low LDL-C measurements at this level through the gold standard beta quantification.

	The exciting new results substantially add to those previously reported from the FOURIER trial. From a clinical perspective, the new data show that the robust lowering of LDL-C with evolocumab on top of statin therapy to a median LDL-C of 31 mg/dL, and much lower in many patients, reduced MACE with an attractive NNT in patients with symptomatic PAD. Evolocumab produces a large reduction in MALE in both patients with PAD and in those without PAD but at risk for it.

	Equally impressive, considering the composite of MACE/MALE in patients with symptomatic PAD and no previous MI or stroke, is that evolocumab produced an absolute risk reduction of 6.3% in just over two years, which translates to a number needed to treat of 16. This number would be expected to drop lower and lower with longer treatment.

	With no apparent major harms to offset the observed efficacy of evolocumab, these findings are highly encouraging for clinicians, and the major barrier to use remains cost/access. These data support the safety and efficacy of LDL-C reduction to very low target levels as a core focus of prevention in not only patients with prior MI or stroke, but also symptomatic PAD.

Lowering LDL-C levels in FOURIER trial patients with PAD had a significant impact on both MACE and MALE.  