PrimeCuts – This Week in the Journals

November 20, 2017

By Alexander Jordan, MD

Peer Reviewed

Love has won another hard-fought victory! In Australia, nearly 13 million people took part in a national survey held on marriage equality, with 61% voting in favor of same-sex marriage [1].

At the same time, mass shootings continue to occur with alarming frequency in the US. In Northern California, a gunman embarked on a deadly rampage that claimed five innocent lives [2]. Further tragedy was averted when the gunman was prevented from entering an elementary school by staff members [3]. Meanwhile, more victims of sexual assault continue to come forward in the wake of the Harvey Weinstein scandal. Al Franken, a popular senator from Minnesota, quickly apologized after Leeann Tweeden publically revealed he sexually harassed her during a comedy tour for US service members in 2006, and is now facing a Senate ethics investigation [4]. In this week’s medical news, Japanese researchers have invented a creative solution to monitor patient adherence to therapy. The antipsychotic Abilify was fitted with ingestible sensors that upload data to a server when ingested, which could allow caregivers to contact patients when they are missing doses and avert future hospital admissions for mental health [5]. Although the digital pill has the potential to improve public health, it has been compared to a “biomedical Big Brother” [6].

Continue reading for highlights from recent articles in the medical literature. 

The ACC/AHA releases new guidelines on the detection, evaluation, and management of hypertension in adults

Since the JNC7 hypertension guidelines were released in 2003, many new studies have been released that may advocate in favor of lower BP goals. These include the multicenter, randomized ACCORD trial that demonstrated that antihypertensive therapy with a BP goal of less than 120 mmHg did not improve cardiovascular outcomes or all-cause mortality when compared to a goal of 140 mmHg in patients with type 2 diabetes. However, patients treated to a goal of <120 mmHg had lower rates of total and nonfatal stroke [7].  In 2015, the randomized, multi-center, open label SPRINT trial demonstrated that a BP goal of 120 mmHg systolic reduced patients’ rates of CVD events and all-cause mortality to a significant degree when compared to a goal of 140 mmHg [8].  Notably, a meta-analysis of 19 separate randomized, controlled trials demonstrated a reduction in major cardiovascular events with more intensive BP control below 140/90 [9].

In light of this, the ACC/AHA has updated its guidelines on the detection and management of hypertension.  These guidelines are written by 18 physicians and scientists of diverse backgrounds selected by the ACC/AHA task force. Many different sources are used to develop recommendations, preferably from randomized controlled trials, although all types of evidence are reviewed.

Most notably, the definitions of Stage 1 and 2 hypertension have changed. Stage 1 hypertension is defined as an SBP of 130-139 or DBP of 80-89, while Stage 2 hypertension now encompasses an SBP ≥ 140 mm Hg or a DBP ≥ 90 mm Hg, differing significantly from classifications introduced in the 2003 JNC 7 report [10, 11]. A lower blood pressure goal of 130/80 is now set for hypertension patients, especially those with CVD or a high 10-year ASCVD risk.  Additionally, the new guidelines identify a subset of patients that could derive benefit from antihypertensive therapy with a goal below <140/90 on the basis of CVD risk. In the JNC 7 guidelines, antihypertensive therapy was recommended on the sole basis of BP alone.

Despite the quality of evidence used, some limitations persist. Concrete evidence of benefit for more intensive BP control in younger, healthier individuals without CVD is difficult to obtain as these studies would have to carry on for decades before adverse cardiovascular events would be detected in the study population. Additionally, these guidelines are created via a committee of physicians whose support for certain recommendations may be altered by their own individual biases [10]. These guidelines will continue to evolve as more studies evaluate the benefit of intensive BP therapy.

Large meta-analysis does not support BP-lowering therapy in patients with systolic BP of 130-139

As the ACC was rolling out its new guidelines, new evidence was published that may refute the new BP goal. A meta-analysis published in JAMA Internal Medicine was carried out to study the relationship between BP levels and the risk of death and cardiovascular disease, given prior concern for causing harm with intensive blood pressure control. Three categories of hypertension were used, with normotension defined as systolic BP below 140 mm Hg, mild HTN as between 140-159 mm Hg, and moderate-to-severe HTN as 160 mmHg or above. Trials were eligible for inclusion if they compared individual antihypertensive drugs against placebo to achieve a certain BP target, or if they directly compared separate BP targets. Trials enrolling patients with heart failure, LV dysfunction, or comparing the effects of two BP drugs with each other were excluded from the trial to reduce the impact of non-BP lowering effects on composite endpoints. Next, any remaining trials deemed to have a high risk of bias were dropped from the final tally.

These selection criteria resulted in the inclusion of 74 separate randomized-controlled trials with approximately 307000 patients. A trial was considered primary preventive if less than half of participants had objective evidence of CVD. Data analysis methods performed included meta-regression, sensitivity analyses, and funnel plots to assess publication bias. Antihypertensive treatment lowered all-cause mortality for patients with mild hypertension (RR, 0.87: 95% CI, 0.75-1.00) and moderate-to-severe hypertension (RR, 0.93; 95% CI, 0.87-1.00). However, in direct contrast with the SPRINT trial [8,12], no reduction in mortality was seen in patients treated with a baseline BP below 140 mm Hg systolic. Similar findings were noted for major cardiovascular events and cardiovascular mortality. Interestingly, patients treated with normotension demonstrated a relative risk reduction in heart failure (RR, 0.88; 95% CI, 0.78-0.98).

Limitations of this study include the fact that many of the trials were industry-sponsored, which may skew the results towards positive outcomes. Additionally, generalizability may be limited by the fact that the mean age of the study was 63.6 years with 60% of the participants being men [12]. Despite this, this study shows that the question of whether or not lower BP targets provide benefit is far from resolved.

Canagliflozin lowers the risk for CV or renal adverse events irrespective of CVD status

Although cardiovascular (CV) mortality is the primary cause of death in type 2 diabetics, reduction of plasma glucose alone has shown little effect on CV disease risk [13].

In the EMPA-REG OUTCOME study and the CANVAS study, the SGLT2 inhibitors empagliflozin and canagliflozin have been shown to decrease the risk of death from CV causes, presumed to be a class effect [14, 15].

The CANVAS study was a multi-center, randomized, industry-sponsored trial designed to study the multiple potential risks and benefits of the drug, including its potential effects on cardiovascular disease risk [15].  Later, the study data was reanalyzed to examine the effects of canagliflozin on similar endpoints in patients with CVD compared to those without. Most of the patients included in the previous CANVAS study were divided into two groups based on their CVD status. Patients without CVD were placed in the primary prevention group, totaling 3486 people ≥ 50 years of age with ≥ 2 CVD risk factors without evidence of disease. The secondary prevention group consisted of those ≥ 30 years of age with known CVD, and totaled 6656 people.  The primary composite outcome of cardiovascular death, nonfatal stroke, or nonfatal MI was significantly less prevalent with canagliflozin when compared to placebo (26.9 vs 31.5/1000 patient-years: HR 0.86; 95% CI, 0.75-0.97). Additionally, a significant decrease in renal complications and hospitalizations for heart failure was noted in comparison with placebo. There was no significant difference in response noted between the primary and secondary treatment groups (p value 0.18).

This study had several important limitations. Although no significant differences between the primary and secondary treatment groups were noted, the study may have not been adequately powered to detect such differences. Additionally, there is a possibility multiple participants included in the primary prevention group may have had CVD, as no attempt was made to detect subclinical CVD. The authors point out that most diabetics are treated with oral agents for far longer than the 3.5 years studied, which may obscure even larger effects on patients over time [16]. When choosing oral agents for type 2 diabetes, physicians can take into account canagliflozin’s potential effect on lowering CVD risk. However, physicians must balance that potential benefit with the increased risk of limb amputation noted in the original CANVAS study [15].

Warfarin may reduce the risk of developing a broad range of malignancies 

 There may be a potential role for warfarin in the ongoing fight against cancer. Warfarin reduces vitamin K pools by inhibiting oxidoreductases, enzymes that transform vitamin K into its active form. This in turn reduces the activity of vitamin K-dependent proteins, which include growth arrest-specific 6, or GAS6. GAS6 binds to multiple receptors of the AXL receptor tyrosine family, which is associated with malignancy [17]. Warfarin prevents this ligand from binding to AXL family receptors, which has been shown to reduce metastasis of pancreatic cancer cells [18]. Warfarin has been shown to increase NK cell cytotoxicity towards metastases in mice [19].

A study from Norway is the first to examine the link in humans, in a large population-based observational cohort study of nearly 1,257,000 individuals.  The group was divided into patients taking warfarin for at least 6 months and those who were not. The primary outcome was a diagnosis of any type of cancer during the 7-year observation period, spanning from January 2006, to December 2012. Results demonstrated a significantly lower rate of cancer diagnosis (IRR, 0.84; 95% CI, 0.82-0.86) in warfarin users. Breast, prostate, and lung cancers were some of the most prevalent in the population and showed significant decreases in warfarin users. Differences in cancer risk were only observed when patients had taken warfarin at least 2 years prior to diagnosis.

The study measured warfarin usage by prescription duration, and thus likely overestimates compliance. Additionally, the database used does not report inpatient and nursing home prescriptions, potentially underestimating the total number of warfarin users. Additionally, warfarin users may differ significantly from nonusers, which was not taken into account by the study [17].  Finally, results of a study of a Norwegian population may not be generalizable to the US population. However, if warfarin does truly confer a lower cancer risk, this could one day lead to a new indication for prescription.


The advent of immunotherapy has revolutionized cancer treatment, however, researchers are unsure of why some patients respond better than others. A new study suggests that melanoma patients who respond to immunotherapy tend to have more diverse gut microbiomes [20].

Cardiovascular adverse events are a significant cause of morbidity and mortality during the perioperative period. Perioperative aspirin may reduce the risk of death or nonfatal MI for those with a history of PCI [21]. 

The debate on whether or not MI patients should be given supplemental oxygen has raged for decades. A new meta-analysis found a significant rise in recurrent MIs in patients receiving supplemental oxygen, indicating it may indeed cause harm [22].

The incidence of sudden cardiac arrest during participation of competitive sports, a much feared event, has not been elucidated. A retrospective study in Canada seems to confirm its rarity, with a rate of 0.76 cases per 100,000 athlete-years [23].

Dr. Alexander Jordan, is a 1st year Internal Medicine Resident at NYU Langone Health. 

Peer reviewed by Rachael Hayes, MD, a Chief Resident in Internal Medicine, NYU Langone Health

Image courtesy of Wikimedia Commons 


[1] Westcott, B. Australia votes ‘yes’ to same-sex marriage. CNN (2017).

[2] Fuller, T. Northern California Gunman Killed Wife Before Shooting Rampage. The New York Times (2017).

[3] Criss, D. How a school custodian saved students from the California shooter. CNN (2017).

[4] Summers, J. & Lee, M. J. Woman says Franken groped, kissed her without consent in 2006. CNN (2017).

[5] Robbins, R. FDA approves the first pill that can alert your doctor when you swallow it. STAT (2017).

[6] Belluck, Pam. First Digital Pill Approved to Worries About Biomedical ‘Big Brother’. The New York Times (2017).

[7] Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. ACCORD Study. N Engl J Med. 2010;362:1575-85. 

[8] Wright JT Jr,Williamson JD,Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. SPRINT Research Group. N Engl J Med. 2015;373:2103-16. 

[9] Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet. 2016;387:435-43.

[10] Whelton PK et al. 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. J Am Coll Cardiol 2017 Nov 13; [e-pub].

[11] Chobanian AV, Bakris GL, Black HR, et al; the National High Blood Pressure Education    Program Coordinating Committee. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-52.

[12] Brunström M and Carlberg B. Association of blood pressure lowering with mortality and cardiovascular disease across blood pressure levels: A systematic review and meta-analysis. JAMA Intern Med 2017 Nov 13; [e-pub].

[13] UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837-53. [Erratum, Lancet 1999;354: 602.]

[14] Zinman B et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. NEJM 2015 Nov 26; [e-pub]

[15] Neal B et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017 Jun 12; [e-pub].

[16] Mahaffey KW et al. Canagliflozin for primary and secondary prevention of cardiovascular events: Results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation 2017 Nov 13; [e-pub].

[17] Haaland GS et al. Association of warfarin use with lower overall cancer incidence among patients older than 50 years. JAMA Intern Med 2017 Nov 6; [e-pub].

[18]. Kirane  A, Ludwig  KF, Sorrelle  N,  et al.  Warfarin blocks Gas6-mediated Axl activation required for pancreatic cancer epithelial plasticity and metastasis.  Cancer Res. 2015;75(18):3699-3705.

[19] Paolino  M, Choidas  A, Wallner  S,  et al.  The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells.  Nature. 2014;507(7493):508-512.

[20] Gopalakrishnan V et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science 2017 Nov 2; [e-pub].

[21]. Graham MM et al. Aspirin in patients with previous percutaneous coronary intervention undergoing noncardiac surgery. Ann Intern Med 2017 Nov 14; [e-pub].

[22] Fu S et al. Oxygen therapy for acute myocardial infarction: A systematic review and meta-analysis. Int J Nurs Stud 2017 Sep; 74:8.

[23] Landry CH et al.  Sudden Cardiac Arrest during Participation in Competitive Sports. N Engl J Med 2017; 377:1943-1953.