Pharmacogenetic guided versus standard warfarin dosing for routine clinical care with its pharmacoeconomic impact: a randomized controlled clinical trial.

BACKGROUND: Empirical use of pharmacogenetic test(PGT) is advocated for many drugs, and resource-rich setting hospitals are using the same commonly. The clinical translation of pharmacogenetic tests in terms of cost and clinical utility is yet to be examined in hospitals of low middle income countries (LMICs). AIM: The present study assessed the clinical utility of PGT by comparing the pharmacogenetically(PGT) guided- versus standard of care(SOC)- warfarin therapy, including the health economics of the two warfarin therapies. METHODS: An open-label, randomized, controlled clinical trial recruited warfarin-receiving patients in pharmacogenetically(PGT) guided- versus standard of care(SOC)- study arms. Pharmacogenetic analysis of CYP2C9*2(rs1799853), CYP2C9*3(rs1057910) and VKORC1(rs9923231) was performed for patients recruited to the PGT-guided arm. PT(Prothrombin Time)-INR(international normalized ratio) testing and dose titrations were allowed as per routine clinical practice. The primary endpoint was the percent time spent in the therapeutic INR range(TTR) during the 90-day observation period. Secondary endpoints were time to reach therapeutic INR(TRT), the proportion of adverse events, and economic comparison between two modes of therapy in a Markov model built for the commonest warfarin indication- atrial fibrillation. RESULTS: The study enrolled 168 patients, 84 in each arm. Per-protocol analysis showed a significantly high median time spent in therapeutic INR in the genotype-guided arm(42.85%; CI 21.4-66.75) as compared to the SOC arm(8.8%; CI 0-27.2)(p < 0.00001). The TRT was less in the PG-guided warfarin dosing group than the standard-of-care dosing warfarin group (17.85 vs. 33.92 days) (p = 0.002). Bleeding and thromboembolic events were similar in the two study groups. Lifetime expenditure was ₹1,26,830 in the PGT arm compared to ₹1,17,907 in the SOC arm. The QALY gain did not differ in the two groups(3.9 vs. 3.65). Compared to SOC, the incremental cost-utility ratio was ₹35,962 per QALY gain with PGT test opting. In deterministic and probabilistic sensitivity analysis, the base case results were found to be insensitive to the variation in model parameters. In the cost-effectiveness-acceptability curve analysis, a 90% probability of cost-effectiveness was reached at a willingness-to-pay(WTP) of ₹ 71,630 well below one time GDP threshold of WTP used. CONCLUSION: Clinical efficacy and the cost-effectiveness of the warfarin pharmacogenetic test suggest its routine use as a point of care investigation for patient care in LMICs.

Anemia in heart failure: still an unsolved enigma.

BACKGROUND: Anemia affects one-third of heart failure patients and is associated with increased morbidity and mortality. Despite being one of the commonest comorbidities associated with heart failure, there is a significant knowledge gap about management of anemia in the setting of heart failure due to conflicting evidence from recent trials. MAIN BODY: The etiology of anemia in heart failure is multifactorial, with absolute and functional iron deficiency, decreased erythropoietin levels and erythropoietin resistance, inflammatory state and heart failure medications being the important causative factors. Anemia adversely affects the already compromised hemodynamics in heart failure, besides being commonly associated with more comorbidities and more severe disease. Though low hemoglobin levels are associated with poor outcomes, the correction of anemia has not been consistently associated with improved outcomes. Parenteral iron improves the functional capacity in iron deficient heart failure patients, the effects are independent of hemoglobin levels, and also the evidence on hard clinical outcomes is yet to be ascertained. CONCLUSION: Despite all the research, anemia in heart failure remains an enigma. Perhaps, anemia is a marker of severe disease, rather than the cause of poor outcome in these patients. In this review, we discuss the current understanding of anemia in heart failure, its management and the newer therapies being studied.

Thyroid Association Ophthalmopathy in Hashimoto's Thyroiditis: a Case Report.

Thyroid associated ophthalmopathy is a constellation of symptoms caused by an autoimmune process involving the orbital tissue. It is common in hyperthyroid patients due to Graves' disease and also reported in euthyroid and hypothyroid Graves' patients with positive thyroid receptor antibodies. But in Hashimoto's thyroiditis, thyroid associated ophthalmopathy is a rarely reported and poorly understood entity. Here we report thyroid associated ophthalmopathy in a patient with hypothyroidism and negative thyroid receptor antibodies who showed heterogeneously hypoechoic thyroid gland on ultrasonography, diffuse lymphocytic infiltrate on fine needle aspiration citology and reduced 99m Tc radioisotope uptake, supporting the diagnosis of Hashimoto's thyroiditis. The patient was treated with levothyroxine and artificial tear drops.