Primecuts – This Week In The Journals

February 22, 2016

Antonin_Scalia_official_SCOTUS_portrait_cropBy Edson Carias, MD

Peer Reviewed

For politicos, the ongoing buzz for potential Supreme Court justice nominees following Justice Scalia’s sudden death last week keeps them in suspense [1].  For music lovers, the suspense was over after winners were announced at this year’s annual Grammy awards.  Lady Gaga paid tribute to David Bowie in grand style, while Kendrick Lamar gave a performance that many are still praising [2].  For movie buffs, awards season will continue with the 88th Annual Academy Awards next week.  Awards for important contributions also extend to medical literature, here at PrimeCuts.  This week, the PrimeCuts “nominees” are:

In patients with Diabetes Mellitus not complicated by renal disease, all anti-hypertensives are created equal

Conflicting guidelines regarding the choice of first line anti-hypertensive in diabetic patients have complicated management decisions. Based on historical data, certain guidelines recommend the use of renin angiotensin system (RAS) inhibitors, which include angiotensin converting-enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs), as first line agents [3]. However, the JNC8 and other European organizations recommend any class of antihypertensives in diabetic patients without renal disease [4,5].

A recently published meta-analysis may help in this decision-making [6].  A thorough database search of randomized controlled trials of RAS blocker effect on outcomes in diabetics yielded 19 randomized controlled trials (RCTs), enrolling 25,414 diabetics, with a follow-up totaling 95,910 patient years.  Most of these RCTs used an ACE-I over ARB and compared RAS inhibition against calcium channel blockers; the remainder compared outcomes against diuretics and β-blockers.  Only three trials enrolled patients with micro-albuminuria or proteinuria.  Outcomes included all-cause mortality, cardiovascular death, myocardial infarction (MI), angina, stroke, heart failure, and revascularization.  Using an intent-to-treat analysis, RAS inhibitors were associated with a similar risk in all outcomes when compared to other antihypertensives.  These findings held in subgroup analyses, with the exception of RAS inhibitors showing a significant reduction in the risk of heart failure compared to calcium channel blockers (0.70 [95% CI: 0.70-0.88]).  As the authors note, the jury is still out when it comes to the choice of first line agent in diabetic patients with renal impairment, as prior studies have defined “renal impairment” and controls differently.  All together, these findings lend credence to recent JNC 8 guidelines and support providers considering any antihypertensive agent as first line in diabetic patients, particularly those without renal impairment.

Targeted thermal vapor ablation for emphysema can improve lung function and quality of life

In patients with severe upper-lobe emphysema, lung volume reduction can result in improved lung function. Unfortunately, surgery carries a high morbidity which limits its widespread use.  Less invasive bronchoscopic interventions consisting of either coil or valve implantation are done at a lobar level and can result in superfluous reduction of less diseased lung in a heterogenous lobe.  Bronchoscopic vapor ablation, a therapy that uses heated water vapor to induce an inflammatory response leading to lung parenchyma scarring and lung volume reduction, is another area of research interest.  The authors of the STEP-UP trial have published 6 month follow up results in an effort to better evaluate selective, sequential vapor ablation as a treatment option.

In this multicenter, parallel-group, open-label, randomized controlled trial, 70 patients with a forced expiratory volume in 1 second (FEV1) between 20% and 45% of predicted were randomized in a 2:1 allocation to receive either two sub-lobar vapor ablation sessions or standard medical management [7]. Primary efficacy endpoints were change in FEV1 and scores on a COPD-specific version of the St. George’s Respiratory Questionnaire (SGRQ-C), a quality of life metric used in respiratory disease.  At 6 months, patients in the ablation group (n=41) showed a significant increase in FEV1 compared to those in the control group (n=23)(14.7% [95%CI: 7.8-21.5]; p<0.0001) as well as a reduction in SGRQ-C points (-9.7 [95%CI: -15.7 to -3.7]; p=0.0021). Overall complication rate from any serious respiratory adverse event was 36% in the treatment group, comprised mostly of Chronic Obstructive Pulmonary Disease (COPD) exacerbations or pneumonia.  As FEV1 can be severely reduced in patients with emphysema, these results show a marked benefit to vapor ablation.  Although several study exclusion criteria may limit the applicability of these results to a wider patient population, future research in segment-preserving vapor ablation therapy is promising.

Mailing nicotine patches improves tobacco cessation rates in adult smokers, even without behavioral support

Nicotine replacement therapy (NRT) is an effective aid in tobacco cessation. Interestingly, many studies evaluating NRT in smoking cessation have included some form of behavioral support [8].

A randomized clinical trial was designed to assess the efficacy of providing free NRT by mail without behavioral support [9].  Participants were recruited via a telephone survey which screened for adults who smoked 10 or more cigarettes per day and answered affirmatively to the question “If nicotine patches were offered for free, would you be interested in receiving them?”  A total of 1,000 participants were found to be eligible for the trial.  Of these, 500 were randomized to the experimental group which received a 5-week supply or NRT and 499 to the control group, which received only follow up, but no additional intervention.  Primary outcome was 30-day smoking cessation at 6 month follow up, evaluated by self-report and/or saliva sample.  Due to sample evaporation and incomplete sample return, only 50.9% of participants in both the treatment and control arm had usable saliva samples for biochemical verification of smoking cessation.  Participants in the treatment arm were more likely to have verified abstinence at 6 month follow up (2.8% vs 1.0%; odds ratio [OR], 2.85; 95% CI, 1.02-7.96; p=.046)..  Treatment group participants were also more likely to self-report abstinence at 6 months (7.6% vs. 3.0%; OR 2.65; 95% CI: 1.44-4.89; p=.002).  At 6 month follow up, the number needed to treat to achieve cessation was 56. Although the improvement in absolute numbers is small, the authors have shown a potentially cost-effective way to improve smoking cessation rates.

Caplacizumab, an anti-von Willenbrand factor immunoglobulin, reduces recovery time in acquired thrombotic thrombocytopenic purpura (TTP)

Acquired TTP occurs when auto-antibodies diminish ADAMTS13 activity, leading to uncleaved von Willebrand factor (vWF) multimers. These uncleaved multimers cause platelet aggregation and microvascular thrombosis, resulting in ischemia and end organ damage.  Although plasma exchange and immunosuppressive therapy improve outcomes, mortality rates remain as high as 10-20% [10]. The TITAN study introduces caplacizumab, an anti-vWF immunoglobulin which prevents platelet aggregation, as a future candidate for treatment of TTP [11].

In this single-blind, parallel-design, multicenter study, 36 patients with TTP were randomized to receive caplacizumab in addition to standard therapy (plasma exchange and immunosuppressants), while 39 patients were randomized to receive placebo (standard therapy). Six patients had undergone a plasma exchange session prior to enrollment. The primary endpoint was time to achieve a platelet count of 150,000 per mm3.  Secondary endpoints included exacerbations, relapse, and duration and volume of plasma exchange. For the 69 patients who had not undergone plasma exchange prior to enrollment, median time to achieving primary endpoint was decreased in the caplacizumab group compared to placebo (3.0 days [95% CI: 2.7-3.9] vs. 4.9 days [95% CI: 3.2-6.6]), representing a significantly reduced time to response (39% reduction; event rate ratio 2.20; 95% CI: 1.28-3.78; p=0.005). Results were similar for the six patients who underwent a plasma exchange session prior to enrollment (2.4 days [95% CI: 1.9-3.0] vs. 4.3 days [95% CI: 2.9-5.7]).  Analysis of secondary endpoints also showed mostly favorable results in the treatment group. Bleeding complications, mostly mild to moderate, were higher in the caplacizumab group, likely due to caplacizumab-induced inhibition of vWF (54% vs. 38%).  Future studies are necessary to evaluate caplacizumab’s effect on a larger patient population.  If reproducible, caplacizumab may change our approach to TTP treatment.

And in the supporting-role category, the nominees this week are:

The BEAT-HF randomized clinical trial questions the effectiveness of tele-monitoring in CHF patients after discharge in decreasing all-cause readmissions [12].

The tTrials showed a moderate benefit in sexual function and some benefit in mood with testosterone treatment in older men [13].

Results of the PUNCH CD Study show safety and durability of a microbiota suspension for the treatment of recurrent C. diff infections [14].

Dr.  Edson Carias, Internal Medicine, NYU Langone Medical Center

Peer reviewed by David Kudlowitz, MD, Internal Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons 


  1. President Obama to “dig into” potential Supreme Court nominations this weekend. ABC News. Feb 19, 2016.
  2. Kendrick Lamar sweeps rap field at Grammys; Taylor Swift wins best album. New York Times. Feb 15, 2016.
  3. Weber MA, Schiffrin EL, White WB, Mann S, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J of Hypertension 2014; 32:1:3-15.
  4. James PA, Oparil S, Carter BL, 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 (JNC 8). JAMA 2014;311:507-20.
  5. Mancia G, Fagard R, Narkiewicz K, et al.  2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013;31:1281-357.
  6. Bangalore S, Fakheri R, Toklu B, Messerli FH. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials. BMJ 2016;352:i438.
  7. Herth FJF, Valipour A, Shah PL, Eberhardt R, et al. Segmental volume reduction using thermal vapour ablation in patients with severe emphysema: 6-month results of the multicenter, parallel-group, open-label, randomized controlled STEP-UP trial. Lancet Respir Med. 2016 Feb [published online].
  8. Hughes JR, Shiffman S, Callas P, Zhang J. A meta-analysis of the efficacy of over-the-counter nicotine replacement. Tob Control 2003;12:1:21-27.
  9. Cunningham JA, Kushnir V, Selby P, Tyndale RF, et al. Effect of mailing nicotine patches on tobacco cessation among adult smokers: a randomized clinical trial. JAMA Inter Med 2016;176:2:184-190.
  10. George JN. Corticosteroids and rituximab as adjunctive treatments for thrombotic thrombocytopenic purpura. Am J Hematol 2012;87:S88-91.
  11. Peyvandi F, Scully M, Kremer Hovinga JA, Cataland S, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med 2016;374:511-522.
  12. Ong MK, Romano PS, Edgington S, et al. Effectiveness of remote patient monitoring after discharge of hospitalized patients with heart failure: the better effectiveness after transition-heart failure (BEAT-HF) randomized clinical trial. JAMA Int Med. Published online Feb 08, 2016.
  13. Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, et al. Effects of testosterone treatment in older men. N Eng J Med 2016;374:611-624.
  14. Orenstein R, Dubberke E, Hardi R, Ray A, et al. Safety and durability of RBX2660 (microbiota suspension) for recurrent Clostridium difficile infection: results of the PUNCH CD study. Clin Infect Dis 2016;62:5:596-602.