Primecuts – This Week in the Journals

February 7, 2018


By Allison Guttman, MD

Peer Reviewed

Last week, Amazon, Berkshire Hathaway and JPMorgan Chase announced their intent to collaborate and establish an independent healthcare company for their employees. Although still in the most primitive stages of planning, their strategy appears to rely on the use of technology to both simplify and increase access to healthcare. This announcement reflects the frustration of American corporations with the current healthcare system and the associated costs of medical treatment [1].

Also, a big shout-out to Punxsutawney Phil who granted us another six weeks of this horrendously cold winter. Thanks, Phil.

On that note, let’s turn our attention to exciting new developments in the medical journals.

Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis 

Osteoporosis, which is responsible for more than 1.5 million fractures in the United States annually, has become an increasing public health concern [2,3]. Current treatments can be subdivided into anti-resorptive agents, such as bisphosphonates, and anabolic agents, such as the recombinant human parathyroid hormone teriparatide [2, 4, 5]. While several previous trials have compared these medication classes, no adequately powered studies to date had examined their efficacy in reducing future fracture risk as a primary endpoint [5].

Recently published in Lancet is the VERtebral fracture treatment comparisons in Osteoporotic women (VERO) study, a multicenter, randomized, double-blind, double-dummy, active-controlled trial comparing the effects of once daily teriparatide to weekly risedronate on new vertebral fractures. Participants were post-menopausal women over the age of 45 with severe osteoporosis defined as a bone mineral density T score ≤ -1.5 SDs and at least two moderate or one severe vertebral fragility fracture.  Greater than 72% of enrolled participants had previously received treatment for osteoporosis, the majority with bisphosphonate agents. Over a 24-month follow-up period, 28 of 516 (5.4%) participants in the teriparatide group had radiographic evidence of a new vertebral fracture compared to 64 of 533 (12.0%) patients in the risedronate group (relative risk 0.44, 95% CI 0.29–0.68; p<0.0001). Additionally, the cumulative incidence of clinical fractures –combined symptomatic vertebral and non-vertebral fragility fractures – was significantly reduced in the teriparatide cohort, though there was no significant difference in the incidence of major non-vertebral fragility fractures between these two treatment groups.

While this study is the first to examine the benefits of these medications using future fracture risk as a primary endpoint, it does not provide data on their effects on other markers of disease that have been applied in other osteoporosis studies, such as bone mineral density and serum markers of bone turnover. Nonetheless, these results confirm what was previously suggested by other clinical trials: teriparatide offers greater clinical benefit than oral bisphosphonate at preventing vertebral and other clinical fractures in post-menopausal women with severe osteoporosis, thus favoring its use in this population [5].

Catheter ablation for atrial fibrillation with heart failure

Atrial fibrillation, one of the most common cardiac arrhythmias, is often associated with heart failure [6-9]. In fact, the prevalence of atrial fibrillation has been shown to increase with heart failure severity, becoming as high as 50% in those with New York Heart Association functional class IV disease [9]. The presence of atrial fibrillation in patients with heart failure has been linked to an increased risk of stroke, hospitalization for heart failure, and death, thus making the management of this arrhythmia an area of clinical investigation [7].

The Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF), published last week New England Journal of Medicine, is a multicenter, open-label, randomized, controlled trial comparing catheter ablation to medical therapy (rate and rhythm control) in patients with paroxysmal or persistent atrial fibrillation and coexisting systolic heart failure. In this study, the composite primary endpoint of death from any cause and overnight hospitalization due to heart failure occurred significantly less in those patients who had undergone catheter ablation compared to medical therapy (51 patients [28.5%] vs. 82 patients [44.6%], P=0.006). Other measured outcomes showed a decrease in all-cause mortality with catheter ablation, which was driven by a significant reduction in cardiovascular death in this cohort. Further findings showed a greater improvement in left ventricular ejection fraction after catheter ablation compared with medical therapy, as well as a greater proportion of patients achieving sinus rhythm at the 60-month follow-up period. Though this study is limited by the absence of blinding to randomization and treatment and the lack of standardized medical therapy, the results do support a clinical benefit in morbidity and mortality to catheter ablation for the management of atrial fibrillation in patients with heart failure [7].

History of childhood kidney disease and risk of adult end-stage renal disease 

The increasing prevalence of both chronic kidney disease (CKD) and end-stage renal disease (ESRD) has prompted the investigation into underlying risk factors for the development and progression of these entities in the hopes of discovering areas for potential intervention [10, 11]. While many of the non-congenital kidney injuries observed in childhood tend to recover, the occurrence of these transient injuries may serve as an independent risk factor for the future development of CKD and ESRD [10].

A large population-based historical cohort study of Israeli adolescent army recruits, published last week in the New England Journal of Medicine, assessed the potential consequences of childhood kidney disease on the future development of ESRD. Patients were analyzed in the study if they demonstrated no clinical or laboratory evidence of compromised renal function during adolescence, and they were excluded if they had any one of a number of known conditions that increases the likelihood of renal impairment. Over a 30-year period, this study showed that individuals with a history of childhood kidney disease – including congenital anomalies, a history of pyleonephritis and glomerular diseases – were at an increased risk for the development of ESRD in adulthood despite having demonstrated normal renal function during adolescence (hazard ratio 4.19 [95% CI, 3.52-4.99]). Furthermore, individuals with a history of childhood kidney disease developed ESRD at a younger age than those individuals without (mean age 41.6±10.7 vs. 48.6±10.0 years; P<0.001) [10]. These findings may be due to damage at the level of individual nephrons that leads to hyperfiltration of remaining functioning nephrons, resulting in accelerated cumulative impairment over time.

This study has several limitations given its historical nature, including the potential for misclassification of childhood kidney disease and the inability to assess the development of other conditions that increase the risk of ERSD (such as diabetes). Despite these limitations, the results suggest that clinically silent anatomical abnormalities or even minor kidney damage during childhood may increase the risk of future ESRD. This may offer the potential for more targeted monitoring in an attempt to mitigate this long-term risk [10].

Risk for arterial and venous thrombosis in patients with myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs), which include diagnoses such as polycythemia vera, essential thrombocythemia and primary myelofibrosis, are diseases of the bone marrow defined by excess clonal blood cell production. While these entities are felt to be associated with an increased risk for the development of both arterial and venous thromboses, no large population-based studies to date have been able to quantify this excess risk compared with matched control participants [12].

A Swedish population-based cohort study recently published in the Annals of Internal Medicine examined the risk of both arterial thromboses (myocardial infarction, ischemic stroke or peripheral arterial thromboembolism) and venous thromboses (pulmonary embolism, deep venous thrombosis, abdominal venous thrombosis or cerebral venous sinus thrombosis) in patients with MPN compared to age- and gender-matched controls. Patients were identified using registries within the Swedish national healthcare system. The results demonstrated an increased risk for both arterial and venous thromboses in patients with MPN across all age groups. The greatest risk occurred in the first 3 months after the diagnosis of MPN (HR 4.0, 95% CI, 3.6-4.4; P<0.001), and this risk remained elevated to a lesser degree over time (HR 2.4, CI 2.3-2.6 and HR 1.8, CI 1.6-1.9 at one and five years after diagnosis, respectively). This decreasing risk of thrombosis over time demonstrated in this study is thought to be a result of the various treatment strategies initiated after the initial diagnosis of MPN was made.

This study confirms, and further quantifies, the prior belief that patients with MPN are at increased risk for the development of thromboses. These findings emphasize the importance of maintaining a high-degree of suspicion in patients with MPN, and the significance of employing appropriate cytoreductive and thromboprophylactic treatments shortly after diagnosis to lower this risk [12]. 

MINICUTS 

A 5-year observational follow-up of a randomized clinical trial published in JAMA this month showed that Roux-en-Y gastric bypass in addition to lifestyle interventions and medical management was better than lifestyle interventions and medical management alone at improving the composite endpoint of glycemic control, lipid-lowering and blood pressure management. However, the extended follow-up demonstrated a decrease in the effect size over time, thus requiring further studies to better understand the long-term sustainability of these findings [13].

The benefits from the viral 2014 social media campaign, the “Ice Bucket Challenge”, which raised $115 million dollars for amyotrophic lateral sclerosis (ALS) charities, are beginning to come into the spotlight. A recent article in JAMA reports that, in part due to this surge of social media-driven funding, investigators have been able to begin enrolling participants in a phase II clinical trial testing the effects of pimozide, an anti-psychotic medication, on delaying disease progression in ALS [14].

A recent prospective cohort study published in Lancet demonstrated that glucocorticoid therapy for Duchenne Muscular Dystrophy delayed the loss of functional milestones and improved overall survival in this population. While glucocorticoid therapy is currently already considered standard of care in this disease, this is the first prospective longitudinal study to demonstrate the long-term effects of this treatment [15].

Dr. Allison Guttman is a 3rd-year internal medicine resident at NYU Langone Health

Peer reviewed by Tamar Schiff, MD, chief resident, internal medicine, NYU Langone Health 

References

  1. Wingfield, N.; Thomas, K.; Abelson, R. “Amazon, Berkshire Hathaway and JPMorgan team up to try to disrupt health care”.The New York Times. Jan 30, 2018. https://www.nytimes.com/2018/01/30/technology/amazon-berkshire-hathaway-jpmorgan-health-care.html
  1. Gopalaswamy V, Dhibar DP, Gupta V, Arya AK, Khandelwal N, Bhansali A, et al. Anabolic Bone Window with Weekly Teriparatide Therapy in Postmenopausal Osteoporosis: A Pilot Study. Endocr Pract. 2017;23(6):657-61. doi: 10.4158/EP161394.OR. PubMed PMID: 28225309. https://www.ncbi.nlm.nih.gov/pubmed/?term=28225309
  1. Jackson RD, Mysiw WJ. Insights into the epidemiology of postmenopausal osteoporosis: the Women’s Health Initiative. Semin Reprod Med. 2014;32(6):454-62. doi: 10.1055/s-0034-1384629. PubMed PMID: 25321423. https://www.ncbi.nlm.nih.gov/pubmed/?term=25321423
  1. Chen JS, Sambrook PN. Antiresorptive therapies for osteoporosis: a clinical overview. Nat Rev Endocrinol. 2011;8(2):81-91. doi: 10.1038/nrendo.2011.146. PubMed PMID: 21894214. https://www.ncbi.nlm.nih.gov/pubmed/?term=21894214
  1. Kendler DL, Marin F, Zerbini CAF, Russo LA, Greenspan SL, Zikan V, et al. Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet. 2017. doi: 10.1016/S0140-6736(17)32137-2. PubMed PMID: 29129436. https://www.ncbi.nlm.nih.gov/pubmed/?term=29129436
  1. Aleong RG, Sauer WH, Davis G, Bristow MR. New-onset atrial fibrillation predicts heart failure progression. Am J Med. 2014;127(10):963-71. doi: 10.1016/j.amjmed.2014.06.006. PubMed PMID: 24931393. https://www.ncbi.nlm.nih.gov/pubmed/?term=24931393
  1. Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L, et al. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med. 2018;378(5):417-27. doi: 10.1056/NEJMoa1707855. PubMed PMID: 29385358. https://www.ncbi.nlm.nih.gov/pubmed/?term=29385358
  1. Martin-Perez M, Ruigomez A, Michel A, Garcia Rodriguez LA. Incidence and risk factors for atrial fibrillation in patients with newly diagnosed heart failure. J Cardiovasc Med (Hagerstown). 2016;17(8):608-15. doi: 10.2459/JCM.0000000000000403. PubMed PMID: 27168141. https://www.ncbi.nlm.nih.gov/pubmed/?term=27168141
  1. Mogensen UM, Jhund PS, Abraham WT, Desai AS, Dickstein K, Packer M, et al. Type of Atrial Fibrillation and Outcomes in Patients With Heart Failure and Reduced Ejection Fraction. J Am Coll Cardiol. 2017;70(20):2490-500. doi: 10.1016/j.jacc.2017.09.027. PubMed PMID: 29145948. https://www.ncbi.nlm.nih.gov/pubmed/?term=29145948
  1. Calderon-Margalit R, Golan E, Twig G, Leiba A, Tzur D, Afek A, et al. History of Childhood Kidney Disease and Risk of Adult End-Stage Renal Disease. N Engl J Med. 2018;378(5):428-38. doi: 10.1056/NEJMoa1700993. PubMed PMID: 29385364. https://www.ncbi.nlm.nih.gov/pubmed/?term=29385364
  1. Wang V, Vilme H, Maciejewski ML, Boulware LE. The Economic Burden of Chronic Kidney Disease and End-Stage Renal Disease. Semin Nephrol. 2016;36(4):319-30. doi: 10.1016/j.semnephrol.2016.05.008. PubMed PMID: 27475662. https://www.ncbi.nlm.nih.gov/pubmed/?term=27475662
  1. Hultcrantz M, Bjorkholm M, Dickman PW, Landgren O, Derolf AR, Kristinsson SY, et al. Risk for Arterial and Venous Thrombosis in Patients With Myeloproliferative Neoplasms: A Population-Based Cohort Study. Ann Intern Med. 2018. doi: 10.7326/M17-0028. PubMed PMID: 29335713. https://www.ncbi.nlm.nih.gov/pubmed/?term=29335713
  1. Ikramuddin S, Korner J, Lee WJ, Thomas AJ, Connett JE, Bantle JP, et al. Lifestyle Intervention and Medical Management With vs Without Roux-en-Y Gastric Bypass and Control of Hemoglobin A1c, LDL Cholesterol, and Systolic Blood Pressure at 5 Years in the Diabetes Surgery Study. JAMA. 2018;319(3):266-78. doi: 10.1001/jama.2017.20813. PubMed PMID: 29340678. https://www.ncbi.nlm.nih.gov/pubmed/?term=29340678
  1. Kuehn BM. Simple Models and Ice Bucket Challenge Fuel Progress in ALS Treatment. JAMA. 2018. doi: 10.1001/jama.2017.20704. PubMed PMID: 29365034. https://www.ncbi.nlm.nih.gov/pubmed/?term=29365034
  1. McDonald CM, Henricson EK, Abresch RT, Duong T, Joyce NC, Hu F, et al. Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study. Lancet. 2017. doi: 10.1016/S0140-6736(17)32160-8. PubMed PMID: 29174484. https://www.ncbi.nlm.nih.gov/pubmed/?term=29174484

One comment on “Primecuts – This Week in the Journals

  • Avatar of A Haddad, MD
    A Haddad, MD on

    Regarding the VERO study mentioned above, comparing teriparatide with risedronate for severe osteoporosis:

    This study did not show that teriparatide “offers greater clinical benefit than oral bisphosphonate at preventing vertebral and other clinical fractures” since there was no statistically significant difference in the incidence of major non-vertebral fractures. And, VERO should not be interpreted as “favoring” the use of teriparatide over bisphosphonates. The study suggests merely that the incidence of vertebral fractures was lower with the former med.

    The primary outcome of VERO was new radiographic vertebral fractures, defined as “a vertebral body height loss of at least 20% (and 4 mm) of a vertebra that was unfractured at baseline”. A secondary outcome of new clinical vertebral fractures (i.e., those with symptoms) is likely more meaningful for patients. The study reports, “the estimated cumulative incidence of clinical fractures at 24 months was 4.8% in the teriparatide group, compared with 9.8% in the risedronate group.” This corresponds to a number needed to treat of 20 patients to prevent one clinical vertebral fracture over 2 years. While this seems quite good, the monthly cost of teriparatide is $3597.48 (according to UpToDate) and that of risedronate is only $209.21.

    Therefore, even if one takes the results of VERO at face value, the cost to prevent one clinical vertebral fracture using teriparatide over residronate is $1,626,369.60. ($3388.27per mo. x 24months x 20 nnt). Could this $1.6 million be spent in other ways to prevent more than one fracture in these patients?

    The VERO study was funded by Lilly, the manufacturer of teriparatide (Forteo). The study authors acknowledge, “the funder designed the study, analysed the data, and had a role in interpreting the data and writing the paper.” Moreover, the cost of the study drug effectively prohibits replication of this study without involvement of the manufacturer (At market price, the cost to supply a similar 683 patients with teriparatide for 2 years would be about $59 million).

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