Primecuts – This Week In The Journals

April 12, 2016

drugsBy Neha Jindal, MD

Peer Reviewed

Pharmaceutical companies made headlines last week when the $150 billion Pfizer-Allergan merger was called off shortly after the Obama administration issued new rules designed to crack down on corporate tax avoidance[1].  This comes on the heels of reports that major drug companies have set significantly higher prices on medications in the last five years.  According to a Reuters analysis, four of the top ten prescribed drugs in the United States had a price increase of over 100% since 2011.  AbbVie Inc. was at the top of the list raising the price of arthritis medication Humira by more than 126% for a typical monthly treatment to $3797.10 compared with $1676.98 in December 2010[2]. In more encouraging money news, $589 million of federal money left over from the successful fight against Ebola will now go to the growing threat of Zika virus[3].

In the face of soaring healthcare costs, the medical community continues to investigate new therapies and optimal use for existing treatments. This week’s primecuts highlights some of these studies.

PCSK9 Inhibitors effective in statin intolerant patients

In their recent study published in JAMA, Nissen et al. use a meticulous protocol to investigate the use of the PCSK9 inhibitor evolocumab among patients with statin intolerance associated with muscle-related adverse effects[4]. This two-staged randomized clinical trial enrolled 511 patients with a history of intolerance to 2 or more statins. Phase A randomized 491 patients to receive either 20mg atorvastatin daily or placebo for 10 weeks, followed by a 2 week washout, followed by a crossover to the alternate treatment for 10 weeks. In phase B, 218 patients who exhibited muscle-related adverse effects while taking atorvastatin but not while taking placebo, or who had experienced a 10-fold increase in creatine kinase level after statin administration were randomized to receive ezetimibe (n=73 patients) or evolocumab (n=145 patients) for 24 weeks. Coprimary endpoints were the mean percentage change in LDL-C level from baseline to the mean of weeks 22 and 24, and from baseline to week 24 levels. At 24 weeks, LDL-C levels were reduced by 16.7% (from 221.1mg/dL to 181.5mg/dL) with ezetimibe and by 52.8% (from 218.8mg/dL to 104.1 mg/dL) with evolocumab (P<.001). Both medications were generally well tolerated, muscle symptoms leading to discontinuation of medication occurred in 5 of 73 ezetimibe treated patients (6.8%) and 1 of 145 evolocumab treated patients (0.7%). This GAUSS-3 trial supports previous studies showing benefit of PCSK9 inhibitors in statin intolerant patients, however this study goes beyond existing literature by using a rigorous protocol to identify patients with true statin intolerance as opposed to relying on patient history alone[5][6] . 

Rectal indomethacin does not prevent post ERCP pancreatitis in Consecutive Patients 

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis is the most prevalent cause of iatrogenic pancreatitis, often leading to hospital admission and considerable morbidity for patients[7].  Since 2003 there have been over six randomized, controlled trials showing that periprocedural NSAIDs reduce the risk of post-ERCP pancreatitis (PEP) by 50-60%[8][9][10][11][12].  A single institution randomized, controlled trial published in the current issue of Gastroenterology contests existing research, finding no evidence of indomethacin’s efficacy in preventing PEP [13]. In this study, 449 patients were randomized to 100mg indomethacin suppository or placebo, inserted after attempted cannulation of the major papilla during ERCP. The primary study outcome of PEP occurred in 16 of 223 (7.2%) patients in the treatment group compared to 11 of 226 (4.9%) patients in the placebo group (P=.33). There was no significant benefit in terms of relative risk reduction for indomethacin vs. placebo.  Secondary outcomes of pancreatitis severity, gastrointestinal bleeding, 30-day hospital readmission, and death were not significantly different.  This trial was stopped early by the Dartmouth Data and Safety Monitoring Committee for futility given no evidence of indomethacin’s efficacy. Limitations of this study include single center enrollment and low event numbers in each study arm.  It is important to note that most research to date shows benefit of rectal NSAIDs in patients at high risk for PEP such as those with history of PEP, difficult cannulation, or Sphincter of Oddi dysfunction.  Levenick et al. intentionally randomized all patients regardless of risk to include those with average risk for PEP as well.  This study delivers concrete evidence for providers to reconsider use of rectal indomethacin to prevent PEP, particularly in average risk patients.

Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol

In the ELITE study, Hodis et al. test the hormone-timing hypothesis[14]. That is, cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation.  In this single center double blind randomized control trial, 643 women without cardiovascular disease were stratified to either early (<6 years since start) or late (>/= 10 years since start) menopause and were randomly assigned to receive either oral 17beta-estradiol (1mg per day, plus 45mg progesterone vaginal gel administered sequentially for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus) for a median of 5 years.  Women with diabetes, uncontrolled hypertension, history of venous thromboembolism, kidney disease, untreated thyroid or liver disease were amongst those excluded.  The primary outcome-rate of change in carotid-artery intima-media thickness (CIMT), differed between early and late postmenopause strata (p=.007 for the interaction). Among women in early menopause, women receiving estradiol (with or without progesterone) had slower mean CIMT increased (0.0078mm per year in the placebo vs. 0.0044mm per year in the estradiol group, P=.008). No significant difference was seen in the late menopause stratum (0.0088mm per year in placebo vs. 0.0100mm per year in estradiol, P=0.29). Secondary outcomes included assessment of coronary atherosclerosis by Cardiac CT. There was no significant difference in CT measurement of coronary atherosclerosis between the placebo and estradiol groups within either postmenopause stratum. Of note, these measurements were only performed in a subset of patients and no baseline measurements were available. No significant difference was found in the frequency of serious adverse events among all groups.

Despite favorable effect of early estrogen use found in the ELITE trial, CIMT remains a surrogate measure of coronary heart disease and this study was not designed or powered to assess coronary events. Clinically significant benefit of early estrogen therapy on the occurrence of myocardial infarction and stroke remains in question.

Bisphosphonates vs. Parathyroidectomy for reducing fracture risk in Primary Hyperparathyroidism

A retrospective cohort study from the Annals of Internal Medicine investigates the relationship of parathyroidectomy and bisphosphonates with skeletal outcomes in patients with biochemically confirmed primary hyperparathyroidism (PHPT)[15].  In 6272 PHPT patients from the Kaiser Permanente Southern California integrated health system followed for fracture, parathyroidectomy was associated with decreased absolute risk for hip fracture at 10 years (absolute risk 20.4 events per 1000 patient, absolute risk reduction -35.5 [95% CI -38.4 to -32.5]) whereas bisphosphonate therapy was associated with an increased risk (absolute risk 85.5 events per 1000 patients, absolute risk difference 29.7 [CI 27.3-31.9]) when compared to observation alone (absolute risk 55.9 events per 1000 patients). Similar trends were seen for any fracture type and when patients were stratified by satisfaction of 2002 consensus guideline criteria for parathyroid removal in PHPT.  Further analysis stratified patients by baseline bone mineral density status. Parathyroidectomy remained protective against all fractures in both osteopenic and osteoporotic patients, while patients in both groups on bisphosphonate therapy had higher rates of fractures when compared to observation alone.

It has been shown that most patients with PHPT managed in the community who meet guideline criteria for parathyroidectomy do not have surgery[16][17]. Although limited by retrospective design, this study brings to light a potential protective effect of parathyroidectomy against fractures in patients with PHPT, regardless of whether they meet guideline criteria for surgery. This study develops a need for prospective randomized trials to further investigate the protective benefit of parathyroidectomy in PHPT.

Also in the journals this week-

Data from the HOPE-3 trial shows statins significantly lower risk of cardiovascular events compared to placebo in an intermediate-risk population without cardiovascular disease[18].

Pioglitazone was associated with a lower risk of stroke or myocardial infarction among patients without diabetes but with insulin resistance and recent ischemic stroke or TIA[19].

Ramakers et al. investigate a growing problem of temporary hearing loss following loud music exposure. They find earplugs were effective in preventing recreational noise-induced hearing loss in their randomized controlled trial looking at 51 people attending an outdoor music festival in Amsterdam[20].

Dr. Neha Jindal is an instructor of medicine, NYU School of Medicine

Peer reviewed by Neil Shapiro, Editor-In-Chief, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


[1] Thomas, K and Bray, C. Pfizer Faces Limited Options after Its Dead Deal with Allergen. The New York Times. Published April 6, 2016.  

[2] Humer, C. Exclusive: Makers took big price increased on widely used U.S. Drugs. Reuters. Published on April 5, 2016.

[3] Taylor, A. White House: $589M to go to fight Zika virus. Associated Press. Published April 6, 2016.

[4] Nissen  SE, Stroes  E, Dent-Acosta  RE,  et al.  Efficacy and tolerability of evolocumab vs. ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA. Published online April 3, 2016.

[5] Stroes  E, Colquhoun  D, Sullivan  D,  et al; GAUSS-2 Investigators.  Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2541-2548.

[6] Moriarty  PM, Thompson  PD, Cannon  CP,  et al; ODYSSEY ALTERNATIVE Investigators.  Efficacy and safety of alirocumab vs. ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9(6):758-769.

[7] Peery AF, Dellon ES, Lund J et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology 2012; 143: 1179-1187.

[8] Elmunzer BJ, Scheiman HM, Lehman GA, et al. A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. New England Journal of Medicine 2012; 366:1414-1422.

[9] Soutoudehmanesh R, Khatibian M, Kolahdoozan S, et al. Indomethacin may reduce the incidence and severity of acute pancreatitis after ERCP. American Journal of Gastroenterology 2007;102:978-983.

[10] Murray B, Carter R, Imrie C, et al. Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography. Gastroenterology 2003; 124: 1786-1791.

[11] KoshbatenM, Khorram H, Madad L, et al. Role of diclofenac in reducing post-endoscopic retrograde cholangiopancreatography pancreatitis. Journal of Gastroenterology and Hepatology 2008; 23:11-16.

[12] OtsukaT, Kawazoe S, Nakashita S, et al. Low dose rectal diclofenac for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a randomized controlled trial. Journal of Gastroenterology 2012; 47: 912-917.

[13] Levenick JM, Gordon SR, Fadden LL et al. Rectal indomethacin does not prevent post-ERCP pancreatitis in consecutive patients. Gastroenterology 2016; 150:911-917.

[14] Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med 2016;374:1221-1231

[15] Yeh MW, Zhou H, Adams AL, Ituarte PH, Li N, Liu IA, et al. The Relationship of Parathyroidectomy and Bisphosphonates with Fracture Risk in Primary Hyperparathyroidism: An Observational Study. Ann Intern Med. Epub ahead of print 5 April 2016.

[16] Wu B, Haigh PI, Hwang R, Ituarte PH, Liu IL, Hahn TJ, et al. Underutilization of parathyroidectomy in elderly patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 2010; 95:4324-30.

[17] Yeh MW, Wiseman JE, Ituarte PH, Pasternak JD, Hwang RS, Wu B, et al. Surgery for primary hyperparathyroidism: are the consensus guidelines being followed? Ann Surg. 2012; 255:1179-83.

[18] Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. Published online April 2, 2016.

[19] Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374:1321-1331.

[20] Ramakers GJ, Kraaijenga VC, Cattani G et al. Effectiveness of Earplugs in Preventing Recreational Noise–Induced Hearing Loss: A Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. Published online April 07, 2016.