Primecuts-This Week in the Journals

November 17, 2015

PrimeCuts 7 min read

File:France Flag Wavy.jpgBy Amy Shen Tang, MD

Friday, November 13th unfortunately proved to be more than an unlucky day for Parisians. What initially sounded like firecrackers outside a soccer match at the Stade de France, with President Francois Hollande in attendance, was quickly realized to be the first suicide bomber detonating explosives. Soon after, gunfire and suicide bombs erupted at Bataclan Music Hall and four other sites simultaneously, culminating in well over 100 deaths and more than 350 wounded. President Hollande declared a state of emergency as world leaders rushed to declare their support for France after what appeared to be a coordinated terrorist attack [1]. The next morning, the militant group ISIS claimed responsibility for the catastrophic attacks, prompting the French military to begin airstrikes against ISIS targets in the Middle East.

While these tragic events may bring back painful memories of 9/11 for many, September 11th also marks the day that the Systolic Blood Pressure Intervention Trial (SPRINT) announced its early termination, declaring that they had “potentially lifesaving information” that intensive blood pressure significantly lowered the rate of cardiovascular events and all-cause mortality in patients without diabetes [2]. The preliminary results of the NIH-sponsored SPRINT trial came as a surprise to the medical community after a related study in patients with diabetes showed no significant difference in rates of cardiovascular events, except stroke, between intensive and standard blood pressure control groups [3].

This week in medical news

Do stricter blood pressure goals decrease cardiovascular events and all-cause mortality in patients without diabetes?

The long-awaited SPRINT trial results were published in New England Journal of Medicine this week [4]. Over 9,000 adults 50 years or older with high blood pressure and increased cardiovascular risk, including patients with chronic kidney disease but not diabetes or prior stroke, were randomized to an intensive treatment group with an SBP target of less than 120 mm Hg or a standard treatment group with a target of less than 140 mm Hg. The study included all major classes of antihypertensive drugs and treatment algorithms were similar to those used in the ACCORD trial.

The study population was elderly and relatively diverse with about a third of the participants women and a third African American. Throughout the 3 years of follow-up, the mean SBP in the two treatment arms remained consistent at around 122 mm Hg in the intensive treatment group and 135 mm Hg in the standard treatment group. Separation in mortality between the groups became evident at approximately two years. The benefits of stricter blood pressure control requires a number needed to treat (NNT) of 61 to prevent the composite primary outcome of first episode of myocardial infarction, acute coronary syndrome, stroke, heart failure, or death from cardiovascular causes. The NNT to prevent death from any cause is 90 and 172 for death from cardiovascular causes. Unsurprisingly, the rates of hypotension and electrolyte abnormalities were more frequent in the intensive treatment group, however the significantly increased rate of acute kidney injury in the intensive group seemed to preferentially affect patients with normal baseline renal function rather than patients with chronic kidney disease, and thus requires closer examination.

The SPRINT trial is the first robust randomized control trial in recent years to challenge the trend towards looser blood pressure control set by the eighth Joint National Committee (JNC 8) just one year ago [5]. However, before clinicians across the country start aggressively lowering blood pressures to an SBP goal of less than 120, we need to more closely examine the realities and consequences behind such a drastic change in paradigm.

Do dipeptidyl peptidase-4 inhibitors or sulfonylureas, when added to metformin, lead to better clinical outcomes in patients with noninsulin-dependent diabetes?

After maximizing the benefits of metformin, it is unclear which oral medication serves as the safest and most effective add-on agent in patients with type 2 diabetes. Sulfonylureas, such as glimepiride, are the most commonly prescribed class of oral hypoglycemics with metformin therapy, but are known to cause adverse events related to hypoglycemia and may also increase cardiovascular events [6]. Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as sitagliptin, have been shown to achieve similar glucose control with a lower risk for hypoglycemia but may increase risk for heart failure in patients with diabetes [7].

An observational cohort study using Taiwan’s National Health Insurance Database compared all-cause mortality, major adverse cardiovascular events (MACE), heart failure hospitalization, and hypoglycemia between more than 10,000 matched patients with diabetes initially on metformin monotherapy then subsequently prescribed DPP-4 inhibitors or sulfonylureas [8]. During 3 years of follow-up, users of DPP-4 inhibitors had lower risks for all-cause death and MACE than sulfonylurea users. No effect was seen, however, on risks for myocardial infarction and hospitalization for heart failure.

While the study results may relieve some concern that DPP-4 inhibitors increase cardiovascular events compared to sulfonylureas, it lacks information on the degree of glycemic control achieved on respective agents, which will likely be a question addressed in future studies.

Do coronary stents improve long-term survival in patients with stable ischemic heart disease?

Eight years ago, the COURAGE trial announced that revascularization with percutaneous coronary intervention (PCI) provided no additional survival benefit to optimal medical therapy at 5 years follow-up for patients with stable ischemic heart disease [9]. On closer analysis, however, the survival curves appeared to separate at 5 years in favor of PCI, suggesting possible late survival benefit. Dr. Steven Sedlis at the New York VA Hospital, along with several colleagues around the country, just completed a follow-up of COURAGE trial participants 15 years from the study’s initiation to show whether revascularization actually does provide any long-term survival benefit in those patients with stable ischemic heart disease [10].

In this extended follow-up analysis, about half of the original 2287 participants of the ACCORD trial consented to inclusion in the extended follow-up cohort. Though there were many significant differences in the baseline characteristics between patients with and without extended follow-up, the study authors noted that none of them, except pulmonary disease, differed significantly between the medical-therapy group and the PCI group within each cohort.

After 15 years, nearly half of the VA patients and one quarter of the non-VA patients in the study had died, with no new trend suggesting a survival benefit with PCI. The main limitation to interpreting this study, however, is the lack of data on patients who received subsequent revascularization during the extended follow-up period. A high rate of revascularization during the extended follow-up period would reduce the likelihood of a divergence in mortality between the two study groups; therefore the late follow-up data may be less reflective of the initial treatment assignment than of a convergence of management strategies over time.

Do continuous chest compressions improve survival or neurologic function in patients with out-of-hospital cardiac arrest?

In out-of-hospital cardiopulmonary resuscitation (CPR), interrupting chest compressions to deliver rescue breaths has recently been posited to potentially reduce blood flow to the brain and thereby reduce CPR effectiveness. Continuous chest compressions with simultaneous asynchronous positive-pressure ventilation may be able to address this hypothetical risk and improve survival and/or neurologic function in patients with out-of-hospital cardiac arrest.

To study this possibility, the NIH sponsored a randomized control study involving 114 emergency medical service (EMS) agencies across North America and over 23,000 adults with non-traumatic, non-asphyxial out-of-hospital cardiac arrest [11]. Patients were systematically randomized, using cluster randomization, by EMS agency with cross-over to the other resuscitation strategy twice per year, to receive continuous manual chest compressions with asynchronous positive pressured ventilation or interrupted chest compressions at a ratio of 30 compressions to two ventilations by EMS providers in the field. There was no significant difference in mortality or neurologic function in the continuous verses interrupted chest compression groups with 9.0% and 9.7%, respectively, surviving to hospital discharge.

On further review, the small difference in the proportion of each minute during which compressions were given suggests that the time spent delivering breaths in between chest compressions in the interrupted compressions group may be too negligible to impact neurologic function or survival outcomes.

Quick-Cuts

Nobel laureate Angus Deaten documents the marked increase in all-cause mortality of middle-aged white non-Hispanic men and women in the United States between 1999 and 2013. Drug and alcohol poisonings, suicide, chronic liver diseases and cirrhosis accounted for the increased death rates among this group. Having less than a high school education was found to be associated with the most marked increases in external cause mortality [12].

A new algorithm that incorporates patients’ hypoglycemia risk, life expectancy, relevant comorbidities, and macrovascular and microvascular complications, may help physicians set individual glycemic targets for patients with diabetes [13].

Chronic statin use significantly decreases immune response to influenza vaccine in elderly individuals. Synthetic statins such as atorvastatin and rosuvastatin cause the most dramatic immunosuppressive effect in this cross-sectional study from a clinical trial of immune response to influenza vaccine [14].

Amy Shen Tang, MD is a 3rd year resident at NYU Langone Medical Center

Peer Reviewed by Anish Parikh, MD Associate Editor, Clinical Correlations

References

  1. Shannon, Victoria. Paris Attacks: What We Know and Don’t Know. The New York Times. 2015 Nov 14. http://www.nytimes.com/2015/11/14/world/europe/paris-attacks-what-we-know-and-dont-know.html?action=click&pgtype=Homepage&region=CColumn&module=MostViewed&version=Full&src=mv&WT.nav=MostViewed
  2. Landmark NIH Study Shows intensive Blood Pressure Management May Save Lives. NHLBI, NIH. 2015 Sep 11. http://www.nhlbi.nih.gov/news/press-releases/2015/landmark-nih-study-shows-intensive-blood-pressure-management-may-save-lives
  3. Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood pressure control in type 2 diabetes mellitus. N Engl J Med. 2010; 362:1575-85. http://www.nejm.org/doi/full/10.1056/NEJMoa1001286
  4. The SPRINT Research Group. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015 Nov 9 [Epub ahead of print]. http://www.nejm.org/doi/full/10.1056/NEJMoa1511939
  5. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee. JAMA. 2014;311(5):507-520. http://jama.jamanetwork.com/article.aspx?articleid=1791497
  6. Roomie CL, Greedy RA, Grijalva CG, Hung AM, Liu X, Murff HJ, et al. Association between intensification of metformin treatment with insulin vs sulfonylrueas and cardiovascular events and all-cause mortality among patients with diabetes. JAMA. 2014;311:2288-96. http://jama.jamanetwork.com/article.aspx?articleid=1878717
  7. Yousefzadeh P, Wang X. The effects of dipeptidyl peptidase-4 inhibitors on cardiovascular disease risks in type 2 diabetes mellitus. J Diabetes Res. 2013; 2013:459821. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654348/
  8. Ou S, Shih C, Chao P, Chu H, Kuo S, Lee Y, et al. Effects on Clinical Outcomes of Adding Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas to Metformin Therapy in Patients With Type 2 Diabetes Mellitus. Ann Intern Med .2015;163:663-672. http://annals.org/article.aspx?articleid=2456123
  9. Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk JK, et al. Optimal Medical Therapy with or without PCI for Stable Coronary Disease. N Engl J Med. 2007;356:1503-16. http://www.nejm.org/doi/full/10.1056/NEJMoa070829
  10. Sedlis SP, Hartigan PM, Teo KK, et al. Effect of PCI on Long-Term Survival in Patients with Stable Ischemic Heart Disease. N Engl J Med. 2015; 373:1937-46. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMoa1505532
  11. Nichol G, Leroux B, Wang H, Callaway CW, Sopko G, Weisfeldt M, et al. Trial of Continuous or Interrupted Chest Compressions during CPR. N Engl J Med. 2015 Nov 9 [Epub ahead of print]. http://www.nejm.org/doi/full/10.1056/NEJMoa1509139
  12. Case A, Deaton A. Rising morbidity and mortality in midlife among white non-Hispanic Americans in the 21st century. PNAS. 2015 Nov 2 [Epub ahead of print]. http://www.pnas.org/content/early/2015/10/29/1518393112.short
  13. Cahn A, Raz I, Kleinman Y, Balicer R, Hoshen M, Lieberman N, et al. Clinical Assessment of individualized Glycemic Goals in Patients With Type 2 Diabetes: Formulation of an Algorithm Based on a Survey Among Leading Worldwide Diabetologists. Diabetes Care. 2015 Oct 30 [Epub ahead of print]. http://care.diabetesjournals.org/content/early/2015/10/06/dc15-0187.long
  14. Black S, Nicolay U, Guidice GD, Rappuoli R. Influence of Statins on Influenza Vaccine Response in Elderly Individuals. J Infect Dis. 2015 Oct 28 [Epub ahead of print]. http://jid.oxfordjournals.org/content/early/2015/10/15/infdis.jiv456.long