As we mourn the death of Nelson Mandela and reflect upon his legacy, let us remember to embrace our differences as we strive toward well being for all. This week, the journals highlight the importance of paying attention to genetic risk factors unique to gender and ethnic backgrounds as we seek to provide optimal therapy for a variety of conditions.
This week’s first article challenges the assumption of gender equality in the use of drug-eluting stents (DES) (1). With a strong nod of support toward evidence-based practice, the Lancet looks at the safety and efficacy of DES placement in women, noting that initial trials on these devices were performed in men (1). Data on 11,557 female patients from 26 randomized trials involving DES conducted in the early 2000s were pooled, and results compared early generation DES (sirolimus- and paclitaxel-eluting) to newer-generation DES (everolimus-, zotarolimus-, biolimus-, and sirolimus-eluting) and to bare-metal stents (BMS). The composite primary safety endpoint of death or myocardial infarction occurred in 10.3% of the patients. Although the differences in deaths among the three groups were small, newer-generation DES were associated with significantly fewer rates of myocardial infarction, definite or probable stent thrombosis, and definite stent thrombosis. The primary efficacy endpoint of rate of target-lesion revascularization was also lowest in women receiving newer-generation DES. However, the authors point out that this was, after all, an observational study on a subgroup of patients, and that correct appraisal of the effects of DES in women would have to be carried out prospectively. Indeed, with gender known to confer different cardiovascular risk factors, prospective trials enrolling women and men in separate but parallel studies may prove most useful. This may pose challenges in recruiting sufficient numbers of patients to each trial but may ultimately prove the safest and most correct approach to study design.
Switching gears from cardiovascular to renal disease, NEJM looks at a combined report of two studies on the association between specific genetic variants and faster progression of chronic kidney disease in black versus white patients (2). In particular, these studies seek more robust data for the association between increased risk of HIV nephropathy, focal segmental glomerulosclerosis, chronic kidney disease due to hypertension, and non-diabetic end-stage renal disease and two genes: MYHN9, the gene encoding nonmuscle myosin heavy chain 9, and APOL1, the gene encoding apolipoprotein L1 whose two variants, G1 and G2 have been associated with resistance to deadly Trypanosoma brucei infections in patients of African origin.
The first of these studies, the African American Study of Kidney Disease and Hypertension (AASK) analyzed the composite primary outcome of doubling of the creatinine level/reduction in GFR by 50% and progression to end-stage renal disease in 693 patients who had initially been randomized to intensive versus standard blood pressure control (goal MAP ≤92 versus 102-107) with either ramipril, metoprolol, or amlodipine. Fifty-eight percent of the enrolled patients reached the composite outcome, with patients carrying two copies of the APOL1 risk variants proving twice as likely to attain both the composite outcome and end-stage renal disease alone. No difference in risk was noted between patients carrying only one copy of the risk variants as compared to the control group. Additionally, no significant difference was noted between patients with two copies of the high-risk MYH9 haplotype and patients who did not carry any risk alleles.
Subsequently, the second study involving APOL1 followed the rate of progression of chronic kidney disease in 2955 diabetic and non-diabetic white and black patients. The Chronic Renal Insufficiency Cohort (CRIC) study enrolled patients with and without the APOL1 high-risk variants. Primary outcome was the rate of decline in GFR and a composite of decline in GFR by 50% and end-stage renal disease. With the results stratified by diabetes status, the fastest decline in renal function and most likely progression to the composite outcome were both highest in high-risk black patients with two copies of the APOL1 risk variant, followed by low-risk carriers of an APOL1 variant, followed by white patients.
Although exact causal relationships between the APOL1 gene variants and progressive renal dysfunction have yet to be uncovered, both AASK and CRIC raise strong arguments for further genetic analysis to identify a specific causal link, as well as for new trials to determine optimal therapeutic strategies for slowing down or even preventing progression of renal disease among high-risk patients.
Finally in the realm of risk stratification, the Annals present a cohort study that proposes a more accurate risk predictor for the development of atrial fibrillation (AF). The current model for calculating a patient’s 10-year risk for developing AF is based on the Framingham Heart Study and factors in age, BMI, systolic blood pressure, presence or absence of treatment for hypertension, PR interval length, age at which a significant cardiac murmur developed, and age of heart failure (4). A follow-up study also included race as a variable, particularly considering that black patients have been shown to have a somewhat lower risk of AF than white patients (5). Noting that premature atrial contractions (PACs) can trigger AF, Dewland and colleagues conducted a prospective, community-based cohort study to look for an association between PACs and AF (3). 1429 patients underwent 24-hour Holter monitoring at enrollment, and ECGs were obtained annually; diagnosis codes on discharge from any hospital admissions were also reviewed for AF. At median follow-up 13 years after enrollment, patients who had developed AF had had a significantly higher baseline frequency of PACs. Hourly PAC counts of 32 or higher showed greater than 90% specificity for 15-year AF risk. Additionally, PAC counts further refined risk stratification within the Framingham risk model. This study may pave the way for investigations into potential benefits of PAC ablation in preventing the negative sequelae of AF.
1. Nature Medicine proposes a pathway for metformin’s mechanism of action: In mice, metformin activates AMP-activated protein kinase, which leads to downstream inhibition of the conversion of acetyl-CoA to malonyl-CoA. Inhibition of this early step in fatty acid synthesis prevents fatty acid accumulation in the liver, which in turn prevents insulin resistance in hepatocytes. Understanding the role of metformin at the molecular level not only sheds light on the effectiveness of a popular drug in the treatment of diabetes but also helps build a rationale for metformin’s use in diseases that share these molecular pathways.
Fullerton MD, Galic S, Marcinko K, et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med. 2013; 19:1649-1654. http://www.nature.com.ezproxy.med.nyu.edu/nm/journal/v19/n12/full/nm.3372.html
Shaw, RJ. Metformin trims fats to restore insulin sensitivity. Nat Med. 2013;19:1570-1572. http://www.nature.com.ezproxy.med.nyu.edu/nm/journal/v19/n12/full/nm.3414.html
2. A meta-analysis in JAMA Internal Medicine reveals a decrease in long-term mortality and myocardial infarctions in patients with multivessel coronary disease undergoing CABG as compared to PCI, taking us a step closer to determining the optimal treatment of this group of patients. The increased stroke risk associated with CABG was mitigated by decreased overall mortality, and the authors argue that these results hold true for diabetics as well. Since the study is limited by its retrospective nature, the availability of trial-level data only and the resultant lack of subgroup analysis, and the lack of inclusion of trials with newer-generation DES, perhaps a patient-level analysis of data from existing trials or even new prospective trials may help support or refute this study that supports a major shift in practice.
Sipahi I, Akay MH, Dagdelen S, et al. Coronary Artery Bypass Grafting vs Percutaneous Coronary Intervention and Long-term Mortality and Morbidity in Multivessel Disease: Meta-analysis of Randomized Clinical Trials of the Arterial Grafting and Stenting Era. JAMA Intern Med. Epub: December 2, 2013. doi:10.1001/jamainternmed.2013.12844 http://archinte.jamanetwork.com/article.aspx?articleid=1783046
3. As reported by the Annals of Internal Medicine, obese patients who are metabolically healthy remain at risk for long-term negative outcomes such as increased mortality and cardiovascular complications. However, normal-weight metabolically unhealthy individuals also face increased risks of mortality and cardiovascular events. Thus, we should continue to promote weight loss in our obese patients and to aggressively treat metabolically unhealthy patients in any BMI range. Better yet, promoting healthy lifestyles to prevent our patients from entering either of these categories may ultimately prove the least confounding.
Kramer CK, Zinman B, Retnakaran R. Are Metabolically Healthy Overweight and Obesity Benign Conditions?: A Systematic Review and Meta-analysis. Ann Intern Med. 2013;159:758-769. http://annals.org/article.aspx?articleid=1784291
Dr. Ilulia Giuroiu is a 3rd year resident, Internal Medicine, at NYU Langone Medical Center
Peer reviewed by Brian Greet, Associate Editor, Clinical Correlations
Image courtesy of Wikimedia Commons
1. Stefanini GG, Baber U, Windecker S, et al. Safety and efficacy of drug-eluting stents in women: a patient-level pooled analysis of randomized trials. Lancet. 2013;382:1879-1888. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61782-1/fulltext
2. Parsa A, Kao L, Xie D, et al. APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease. N Engl J Med. 2013;369:2183-2196. http://www.nejm.org/doi/full/10.1056/NEJMoa1310345#t=article
3. Dewland TA, Vittinghoff E, Mandyam MC, et al. Atrial Ectopy as a Predictor of Incident Atrial Fibrillation: A Cohort Study. Ann Intern Med. 2013;159:721-728. http://annals.org.ezproxy.med.nyu.edu/article.aspx?articleid=1784287
4. Schnabel RB, Sullivan LM, Levy D, et al. Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study. Lancet. 2009;373:739-745. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60443-8/fulltext
5. Chamberlain AM, Agarwal SK, Folsom AR, et al. A Clinical Risk Score for Atrial Fibrillation in a Biracial Prospective Cohort (From the Atherosclerosis Risk in Communities [ARIC] Study). Am J Cardiol. 2011;107:85-91. http://www.sciencedirect.com/science/article/pii/S0002914910017327