Hotcakes: Exercise, Aspirin, Fish Oil and Hypertension

November 29, 2018 | By Sarah Phoebe Roberts

Tony Breu MD joins us for some hotcakes, and “cold cakes” including: how aspirin and zodiac sign affect the treatment of acute MI, a recent study on how exercise is probably still good for you, the recently announced REDUCE-IT trial, and the evidence (or lack thereof) for the treatment of hypertensive urgency. Welcome to another edition of Hotcakes and Hot Takes, where we discuss the most interesting articles and news that we have been reading. Special guest is the prolific Dr. Tony Breu (@tony_breu) who is an Assistant Professor of Medicine at Harvard Medical School and a Hospitalist and Director of Internal Medicine Resident Education at the VA Boston Healthcare System. He is known for his series on “Things We Do For No Reason” as well as his thought-provoking “Tweetorials” online. ACP members can visit https://acponline.org/curbsiders to claim free CME-MOC credit for this episode and show notes (goes live 0900 EST on day of release).

Credits

Written and Produced by: Sarah Phoebe Roberts MPH, Christopher Chiu MD

CME Questions: Christopher Chiu MD

Hosts: Matthew Watto MD, Stuart Brigham MD, Paul Williams MD, and Christopher Chiu MD

Guest Presenter and Content Planning: Anthony Breu MD

Editor: Christopher Chiu MD

Cover-Art: Christopher Chiu MD

Time stamps

• 00:00 Disclaimer, intro, guest bio
• 05:53 Discussion on Tweetorials
• 08:00 Cold Cake: ISIS-2 and the treatment of acute MI with aspirin
• 14:04 ISIS-2 and zodiac subgroup analysis
• 16:19 What is the relationship between cardiorespiratory fitness on mortality?
• 24:40 Discussion of the REDUCE-IT study
• 33:00 Cold Cake: VA Cooperative study and the evidence for treating essential hypertension
• 36:42 TWDFNR and the treatment of hypertensive urgency
• 46:36 Wrap-up and outro

Cold Cakes, Hotcakes and Hot Takes

ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. “Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.” Lancet 2.8607 (1988): 349-60.

What’s the clinical question? Who is the patient population?

Compared to placebo, what treatment is more effective at preventing vascular mortality among patients with recent suspected acute myocardial infarction (AMI): 1.5 million units (MU) of IV streptokinase administered once, 162.5 mg aspirin taken orally QD for one month, both treatments together, or neither treatment.      

Bottom line?

Compared to placebo, aspirin alone and streptokinase alone significantly reduced short-term (five weeks post-discharge) and longer-term (15 months) vascular mortality. However, optimal effectiveness was achieved by administering aspirin and streptokinase together. This was the first study to show clinical efficacy of aspirin in reducing vascular mortality in acute MI.

Subgroups analysis is dangerous

Analysis by zodiac sign underscores the potential failings of subgroup analysis and the likelihood of spurious associations by chance alone as statistical significance was lost in the combination of the Libra and Gemini participants.

Mandsager, Kyle, et al. Association of Cardiorespiratory Fitness With Long-term Mortality Among Adults Undergoing Exercise Treadmill Testing. JAMA Network Open 1.6 (2018): e183605-e183605.

What’s the clinical question? Who is the patient population?

What is the relationship between cardiorespiratory fitness, as measured by performance on exercise treadmill testing (ETT or ‘stress testing’), and all-cause mortality among adults?

Bottom line?

Hazard ratios calculated for each performance category confirmed that better performance on ETT was associated with a reduced risk of mortality. There was an 80% reduction in mortality risk for those who performed at the ‘elite’ level compared to participants in the ‘low’ performance category. Extremely high CRF (i.e. ‘elite’ performance) is associated with the greatest reduction in mortality risk.     

Editorial

See also this NEJM editorial pointing out that this study allays previous concern re: “U shaped” curve suggesting increased mortality in elite athletes due to myocardial fibrosis, atrial fibrillation, and coronary artery calcification.

Original Press Release at time of recording – Amarin Corporation. REDUCE-ITTM CARDIOVASCULAR OUTCOMES STUDY OF VASCEPA® (ICOSAPENT ETHYL) CAPSULES MET PRIMARY ENDPOINT. September 24, 2018.

What’s the clinical question? Who is the patient population?

The pharmaceutical company Amarin Corporation has released initial results from the REDUCE-IT™ trial, which examines the effect of their fish-oil derived product Vascepa® (icosapent ethyl, also known as AMR101) on cardiovascular (CV) event incidence. Study participants are patients at higher risk of CV events who are currently taking statin drugs to treat hyperlipidemia.

Bottom line?

REDUCE-IT trial participants with controlled LDL but still elevated triglycerides (150-499 mg/dL range) who were assigned to the icosapent ethyl group experienced an approximately 25% reduction in risk of CV events such as MI, stroke, and angina.

See also:

• (Update) Study now released: Bhatt, Deepak L., et al. “Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.” New England Journal of Medicine (2018). As well as the accompanying editorial here.
• Lead researcher, Dr Deepak Bhatt, Prof Harvard, Brigham and Women’s; over 750 publications; funded by Amarin. Hear him discuss the trial here
• Review of EPA’s “pleiotropic effects” Postgrad Med 2017
• Cochrane Review 2018: Moderate to high quality evidence suggests no CV benefit from EPA and DHA (Omega 3) with prior data mainly from trials at high risk for bias.
• Current AHA recommendation for clinical use of Omega 3 Circulation 2017.
• Amarin sued FDA so it could market Vascepa® for off label use
• Vascepa® costs $242.32 for 120 capsules

Freis E, Arias LA, et al. “Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129mmHg.” JAMA 202 (1967): 1028-1034. PDF version here.

What’s the clinical question? Who is the patient population?

This study, published in 1967, examined whether treating essential hypertension with hydrochlorothiazide + reserpine + hydralazine hydrochloride was superior to placebo among adult male patients. Adverse health events tracked for ~2 years.     

Bottom line?

Approximately 39% of the placebo group experienced severe adverse health events, including 4 deaths, compared to ~3% of the medication group (no patients in the treatment group died). This study was important in establishing that treating essential hypertension is critical to the prevention of adverse outcomes such as stroke, MI, heart failure, renal failure, hospitalization and death.

Was this study ethical?

By current standards, the ethics of this study are debatable. At the very least, it is likely that it would have been stopped earlier given the enormous difference in outcomes between the two arms.

Breu, Anthony C., and R. Neal Axon. “Acute Treatment of Hypertensive Urgency.” Journal of hospital medicine (2018).

What’s the clinical question? Who is the patient population?

Is it necessary to treat hypertensive urgency (SBP ≥ 180, DBP ≥ 120, with no evidence of end-organ damage) among adult patients in hospital settings with medication designed to rapidly reduce blood pressure? What is the evidence?

Bottom line?

Unless hypertension is accompanied by end-organ damage (and therefore, actually hypertensive emergency), acutely lowering a patient’s blood pressure is unnecessary and may even be harmful. If reversible treatable causes such as missed doses of outpatient medications or pain cannot be immediately identified, allow the patient to rest for 30 minutes, then reassess their blood pressure with correct technique. If still elevated, consider augmentation of their outpatient regimen and arranging close outpatient follow-up after discharge.

Goals and Learning Objectives

Goals:

Listeners will learn about relevant medical literature, with emphasis on breaking news and recently published research.

Learning objectives:

After listening to this episode listeners will…

1. Learn about important journal articles and their salient points
2. Learn how to critically analyze journal articles in a practical way
3. Learn what medical news is being widely reported in the lay media and the underlying evidence in the literature
4. Review the current literature on the following subjects: (1) How does cardiorespiratory fitness affect mortality, (2) What is the effect of icosapent ethyl on secondary prevention of cardiovascular disease, (3) What is the evidence for the treatment of hypertensive urgency.

Disclosures:

Dr. Breu reports non relevant financial disclosures. The Curbsiders report no relevant financial disclosures.