Primecuts – This Week in the Journals

November 1, 2019

By Gabriela Abrishamian-Garcia, MD

Peer Reviewed

With medicine advancing at such a rapid pace, it is crucial for physicians to keep up with the medical literature. This can quickly become an overwhelming endeavor given the sheer quantity and breadth of literature released on a daily basis. Primecuts helps you stay current by taking a shallow dive into recently released articles that should be on your radar. Our goal is for you to slow down and take a few small sips from the medical literature firehose.

Comprehensive comparative effectiveness and safety of first-line antihypertensive drug classes: a systematic, multinational, large-scale analysis

With so many available anti-hypertensive agents, including ACE inhibitors, ARBs, DHP and non-DHP calcium channel blockers, thiazide or thiazide-like diuretics, there remains uncertainty about the optimal first-line choice for treatment of hypertension. This systematic, large scale study (LEGEND-HTN) was designed to compare effectiveness and safety across many anti-hypertensive drugs and outcomes. Observational data from 4.9 million patients from 1996 to 2018 was taken from a global network of administrative claims and electronic health record databases, which was used to estimate the relative risks of three primary outcomes (acute myocardial infarction, hospitalization for heart failure, and stroke), as well as multiple secondary effectiveness and safety outcomes.

Using hazard ratios comparing classes and outcomes across all databases, most estimates revealed no differences between the different drug classes. However, thiazides and thiazide-like diuretics showed better primary effectiveness and safety profiles than ACE-inhibitors as initial treatment with lower risk for acute MI (HR 0.84, 95% CI 0.75–0.95), hospitalization for heart failure (0.83,0.74–0.95), and stroke (0.83, 0.74–0.95). Non-DHP calcium channel blockers were significantly inferior to the other four classes. Given the large and heterogeneous patient population in this analysis, these results may better represent real-world practice outcomes than limited patient population and study design in randomized controlled trials comparing anti-hypertensive drugs head-to-head. 

Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction

Sacubitril-valsartan has been shown to reduce risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure with a reduced ejection fraction, however, its effects in patients with heart failure with preserved ejection remains unclear. In this randomized double-blinded study, 4822 patients with HFpEF were randomized to receive sacubitril-valsartan or valsartan alone. Patients were included if they had (NYHA) class II-IV heart failure, EF>45%, elevated level of natriuretic peptides, and structural heart disease.

Sacubitril–valsartan compared to valsartan alone did not result in a statistically significant lower rate of primary outcomes among patients with HFpEF. There were 894 primary events in 526 patients in the sacubitril–valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril–valsartan group and 8.9% in the valsartan group (HR 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). Subgroup analysis suggested some benefit with decreased total heart failure hospitalizations plus cardiac death in patients of the lower end of ejection fraction (45-50%) (rate ratio 0.76, CI 0.63 to 0.92) and women (0.66, CI 0.49-0.88). Although there were no significant differences in outcomes in the sacubitril-valsartan group in this particular study, there may be a role for this drug in women and with patients with mildly reduced ejection fraction, which should be assessed in future studies.

Prognostic Implications of Congestion on Physical Examination Among Contemporary Patients With Heart Failure and Reduced Ejection Fraction

Physical exam findings in patients with heart failure with reduced ejection fracture may provide more prognostic value than previously thought. This study analyzed 8380 participants from the PARADIGM-HF study (angiotensin receptor-neprilysin inhibitor vs. ACE inhibitor in heart failure) with a documented baseline physical exam to determine the association between the number of signs of congestion (jugular venous distention, edema, rales, and third heart sound) with the primary outcome (cardiovascular death or HF hospitalization) and all-cause mortality.  It also assessed the effects of sacubitril-valsartan on congestion.

After adjusting for baseline natriuretic peptides, MAGGIC risk scores (Meta-Analysis Global Group in Chronic Heart Failure), and NYHA class, increasing congestion was associated with all outcomes (P<0.001). Sacubitril-valsartan reduced the risk of the primary outcome irrespective of clinical signs of congestion at baseline (P=0.16), and treatment with the drug improved congestion to a greater extent than did enalapril (P=0.011). Change in congestion strongly predicted outcomes even after adjusting for baseline congestion (P<0.001).

This study emphasizes the importance of the physical exam, as it was shown to provide significant independent prognostic value after adjusting for confounding variables in patients with HFrEF. Reducing congestion as assessed by serial physical exams in the outpatient setting is associated with improved quality of life and fewer cardiovascular events, including mortality.

Dapagliflozin approved to reduce risk for heart failure hospitalization in Type 2 Diabetes

Last week, the FDA approved the SGLT2 inhibitor, dapagliflozin, as a drug to reduce risk for heart failure hospitalization in patients with type 2 diabetes. This approval was based on a randomized control trial (DECLARE-TIMI 58 in January 2019) of patients with DM2 who were at risk for atherosclerotic vascular disease and the study found that the drug resulted in lower rates of cardiovascular death or hospitalization from heart failure.

Influenza drug now indicated for high risk patients

Just in time for flu season, the FDA has expanded approval for baloxavir marboxil (Xofluza®) , an endonuclease transcription inhibitor, for use in patients with acute, uncomplicated influenza who are high risk for developing serious complications from the flu (i.e. patients with chronic conditions.) The drug was previously approved in 2018 for uncomplicated flu in otherwise healthy patients, but data from a phase III trial in patients considered high risk showed decreased time to symptom improvement relative to placebo and was comparable to oseltamavir.

Metoprolol doesn’t reduce COPD exacerbations in Moderate-to-Severe Disease

There was some thought based on observational data that beta blockers may reduce the risk of exacerbations and death in patients with COPD but a recent randomized trial showed that this is not the case. The study randomized COPD patients (without any other indication to take a beta blocker) to receive metoprolol vs. placebo and found that hospitalization for exacerbation was actually more common in patients treated with metoprolol. These findings do not suggest that it is unsafe for patients with COPD to be on a beta blocker if they have another health condition in which a beta blocker is indicated.

Non-pharmacologic Therapies May Be Better for Patients with Dementia and Agitation/Aggression

Outdoor activities may be more effective than anti-psychotics for treating physical aggression in patients with dementia. A recent meta-analysis comparing pharmacologic vs. non pharmacologic methods for treating neuropsychiatric symptoms of dementia found that non-pharmacologic methods (i.e. exercise, massage, etc) were more effective at reducing aggression and agitation.  The results of this study suggest that more emphasis should be placed on non-pharmacologic methods of treating patients with dementia.

Dr. Gabriela Abrishamian-Garcia is a resident physician at NYU Langone Health

Peer reviewed by Gabe Perreault, MD, VA Outpatient Chief Resident, NYU Internal Medicine Residency Program, NYU Langone Health

Image courtesy of Wikimedia Commons


[1] Suchard, M.J.S. Comprehensive comparative effectiveness and safety of first-line antihypertensive drug classes: a systematic, multinational, large-scale analysis. The Lancet. 24 Oct 2019.

[2] Solomon, S.D., et al., Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med 2019; 381:1609-1620.

[3] Selvaraj, S., et al., Prognostic Implications of Congestion on Physical Examination Among Contemporary Patients With Heart Failure and Reduced Ejection Fraction. Circulation. 2019;140:1369–1379.

[4] Wiviott, S.D., et al Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2019; 380:347-357.

[5] Hayden FG et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescentsN Engl J Med 2018 Sep 6; 379:913. (

[6] Dransfield, M.T., et al., Metoprolol for the Prevention of Acute Exacerbations of COPD. N Engl J Med 2019.

[7] Watt, J.A., et al., Comparative Efficacy of Interventions for Aggressive and Agitated Behaviors in Dementia: A Systematic Review and Network Meta-analysis. Ann Intern Med 2019.