A New Drug For Heart Failure

ACE inhibitors are standard of therapy in patients with heart failure as clinical trials have shown mortality benefit with these drugs. A trial published in NEJM compared a new drug LCZ696 with enalapril (an ACE Inhibitor) and found this new drug to far better.

This trial randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy.

The trial was stopped early (after a median follow-up of 27 months) because there was clear evidence of benefit of LCZ696 over enalapril. The primary outcome (a composite of death from cardiovascular causes or hospitalization for heart failure) had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001).

The incidence and type of adverse effects were different between the two drugs; the LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema while enalapril group have higher proportions with renal impairment, hyperkalemia, and cough.

LCZ696 is an investigational combination drug consisting of two antihypertensives (blood pressure lowering drugs), valsartan and AHU-377, in a 1:1 mixture. It is being developed by Novartis. The combination is often described as a dual-acting angiotensin receptor-neprilysin inhibitor although the two effects are achieved by two different molecules. AHU-377 is a prodrug that is activated to LBQ657 by de-ethylation via esterases.LBQ657 inhibits the enzyme neprilysin, which is responsible for the degradation of atrial and brain natriuretic peptide, two blood pressure lowering peptides that work mainly by reducing blood volume.

On the financial side, projections on peak sales from the company's own bullish $2 billion to $5 billion. The highest estimate is by Deutsche's awestruck of $10 billion while the lowest is by EvaluatePharma which pegged nearer-term 2020 sales at a much more modest $1.3 billion.

Colchicine - Postpericardiotomy Syndrome - Postop AFib

Not surprisingly, increased morbidity and perhaps increased mortality, is associated with postpericardiotomy syndrome as well as post-operative development of atrial fibrillation and pericardial and pleural effusions. Colchicine may prevent these complications and COPPS-2 trial looked at this possibility.

This trial was reported in JAMA and also presented at ESC

The results were as below:

PRIMARY ENDPOINT: “The primary end point of postpericardiotomy syndrome occurred in 35 patients (19.4%) assigned to colchicine and in 53 (29.4%) assigned to placebo (absolute difference, 10.0%; 95% CI, 1.1%-18.7%; number needed to treat = 10).

SECONDARY ENDPOINT: “There were no significant differences between the colchicine and placebo groups for the secondary end points of postoperative AF (colchicine, 61 patients [33.9%]; placebo, 75 patients [41.7%]; absolute difference, 7.8%; 95% CI, −2.2% to 17.6%) or postoperative pericardial/pleural effusion (colchicine, 103 patients [57.2%]; placebo, 106 patients [58.9%]; absolute difference, 1.7%; 95% CI, −8.5% to 11.7%), although there was a reduction in postoperative AF in the prespecified on-treatment analysis (placebo, 61/148 patients [41.2%]; colchicine, 38/141 patients [27.0%]; absolute difference, 14.2%; 95% CI, 3.3%-24.7%).

ADVERSE EVENTS: “Adverse events occurred in 21 patients (11.7%) in the placebo group vs 36 (20.0%) in the colchicine group (absolute difference, 8.3%; 95% CI; 0.76%-15.9%; number needed to harm = 12), but discontinuation rates were similar”.

Platelet Glycoprotein IIIa and Aspirin Resistance

Aspirin is the mainstay of treatment for the prevention of cardiovascular disease. It acts by irreversibly inhibiting COX1 enzymes and hence blocking arachidonic acid-thromboxane pathway. Due to lack of a nucleus, platelets cannot generate new COX1 and hence COX1 is inhibited for the lifetime of platelets (8 days). Aspirin treatment results in marked decrease in the excretion of urinary metabolites of thromboxane; the residual excretion is thought to be of endothelial origin where presence of nucleus results in formation of new COX1.

Despite adequate aspirin therapy, a significant number of individuals continue to have higher platelet reactivity and incomplete inhibition of platelet function. Such individuals are also at increased risk of future cardiovascular events. However, the underlying mechanisms that result in higher residual platelet reactivity after aspirin treatment are unclear and are being extensively explored by several researchers.

To identify mechanism of aspirin resistance, this study examined the differences in proteome of 2 aspirin resistant and 4 aspirin sensitive individuals and found that the levels of glycoprotein IIIa were higher in aspirin resistant individuals than in those without aspirin resistance.

Due to small sample size, it is difficult to rule-out the possibility of a type I error, however, considering the role of glycoprotein IIIa in platelet biology, it is conceivable that protein may play a role in aspirin resistant although exact mechanism remains unknown.

Benefits of Aspirin Use in the General Population

Aspirin is perhaps the most commonly used drug world-wide for various ailments. Its prophylactic use in secondary prevention of cardiovascular diseases is well-established, however its use for cardiovascular disease prophylaxis in primary prevention has not been as clear. In particular, some recent meta-analysis has raised concern that aspirin use may not be beneficial for primary prevention of cardiovascular diseases. In support of a role of aspirin use in general population, a systematic review recently concluded:

“For average-risk individuals aged 50–65 years taking aspirin for 10 years, there would be a relative reduction of between 7% (women) and 9% (men) in the number of cancer, myocardial infarction or stroke events over a 15-year period and an overall 4% relative reduction in all deaths over a 20-year period”

In other words, aspirin use is beneficial for both cardiovascular and cancer standpoint, its takes three years to see a beneficial effect, and effect lasts long after aspirin use has been discontinued.

Platelet Diameters in Inherited Thrombocytopenia

An interesting article providing a systematic evidence for what is well-known but not reported in a systematic manner.

“To improve knowledge in this field, we evaluated platelet size on blood films obtained from 376 patients with all 19 forms of IT identified so far and found that these conditions differ not only in mean platelet diameter, but also in platelet diameter distribution width and the percentage of platelets with increased or reduced diameters………….. We also measured platelet diameters in 87 patients with immune thrombocytopenia and identified cutoff values for mean platelet diameter and the percentage of platelets with increased or reduced size….”

iRegulon: From a Gene List to a Gene Regulatory Network Using Large Motif and Track Collections

Identifying master regulators of biological processes and mapping their downstream gene networks are key challenges in systems biology. iRegulon is a software that implements a genome-wide ranking-and-recovery approach to detect enriched transcription factor motifs and their optimal sets of direct targets. The software can be obtained from this website

 

Circleator: Flexible Circular Visualization of Genome-Associated Data

Came through this interesting package which builds graphs similar to Circos but just a little easier

“Circleator is a Perl application that generates circular figures of genome-associated data. It leverages BioPerl to support standard annotation and sequence file formats and produces publication-quality SVG output. It is designed to be both flexible and easy to use. It includes a library of circular track types and predefined configuration files for common use-cases, including: 1. visualizing gene annotation and DNA sequence data from a GenBank flat file,
2. displaying patterns of gene conservation in related microbial strains,
3. showing SNPs and indels relative to a reference genome and gene set, and
4. viewing RNA-Seq plots.”

Greater Collagen-Induced Platelet Aggregation Following Cyclooxygenase 1 Inhibition Predicts Incident Acute Coronary Syndromes

Platelets have several pathways that initiate aggregation such as thrombin-, collagen-, thromboxane-, and ADP-mediated pathways. Individuals vary widely in their ability to have platelet aggregation through each of these pathways. Furthermore, this variability is not correlated. In other words, an individual may have low aggregation though one pathway but may have high aggregation through another pathway. This phenomenon may be more important when we try to measure platelet aggregation the laboratory to assess whether there is increased risk of in vivo platelet aggregation (and hence cardiovascular events).

Collagen is one of the first agonists that initiates platelet aggregation at the site of vessel wall injury. Therefore, examining an association of collagen-mediated platelet aggregation with subsequent cardiovascular events makes sense. Moreover, if we can decrease variability in platelet aggregation by blocking one or another pathway, we may be better able to assess activation through collagen pathway.

Aspirin is commonly used for prevention of cardiovascular disease and works by inhibiting thromboxane-pathway an dis very effective in completely inhibiting activity through this pathway. Thus aspirin can be used to inhibit variability through one pathway and effect of collagen can be studied with fewer interactions. We followed the same logic in this paper where we examined platelet aggregation after 2-week aspirin therapy in healthy individuals. Most of these individuals did not use aspirin after the 2-week study period. During follow-up increased collagen-mediated platelet aggregation was significantly associated with acute coronary syndrome.

“After COX1 pathway inhibition, collagen-induced aggregation was significantly greater in participants with ACS compared with those without (29.0 vs. 23.6 ohms, p < 0.001). In Cox proportional hazards models, this association remained significant after adjusting for traditional cardiovascular risk factors (HR = 1.10, 95%CI = 1.06-1.15; p < 0.001).”

The Science Publishing Complex – <1% publish 42% of all papers

There are not as many successful scientists as we think there are – most are just trying (or leaving).

“Using the entire Scopus database, we estimated that there are 15,153,100 publishing scientists (distinct author identifiers) in the period 1996–2011. However, only 150,608 (<1%) of them have published something in each and every year in this 16-year period (uninterrupted, continuous presence [UCP] in the literature). This small core of scientists with UCP are far more cited than others, and they account for 41.7% of all papers in the same period and 87.1% of all papers with >1000 citations in the same period.”