Optimum INR intensity and therapeutic INR control in patients with mechanical heart valve prosthesis on warfarin oral anticoagulation at Dr George Mukhari academic hospital: a three-year retrospective study

Background: Available evidence suggest that the optimum prothrombin time-international normalised ratio (PT-INR) intensities recommended for anticoagulation of patients with mechanical heart valve prosthesis may not apply to all race groups. Optimal PT-INR target ranges and effectiveness of warfarin oral anticoagulation were determined among black South African patients fitted with St Jude bileaflet mechanical heart valve prosthesis  (SJBMHVP) at Dr George Mukhari Academic Hospital (DGMAH).Methods: A convenience sample of 95 medical records of patients fitted with SJBMHVP from 1994 until 2013 was reviewed. Optimum PT-INR target ranges were estimated using two different methods: the classical two PT-INR target level method and the alternative, PT-INR specific incident rate method. The quality of warfarin anticoagulation was assessed using the fraction in therapeutic range method.Results: Optimum PT-INR target ranges for all participants fitted with SJBMHVP in the aortic position was estimated to be 2.0–3.5 and 2.6–3.5, respectively, by the classical and alternative methods. That of the patients with mitral valve replacement was estimated to be in the range 2.6–3.5 by the classical method and that of patients with double heart valve  replacement was estimated to be < 3.5 by both methods. The quality of warfarin anticoagulation of participants with SJBMHVP replacement wasfound to be inadequate as indicated by percentage time in treatment range (TTR) of 49.7% for all study participants compared with the ideal TTR of 70% and above.Conclusion: Optimum Caucasian-based PT-INR intensities recommended for oral anticoagulation of patients fitted with mechanical heart valve prosthesis are applicable to black patients fitted with SJBMHVP at DGMAH.Keywords: black South African patients, heart valve prosthesis, optimal PT-INR, time in treatment range, warfarin oral anticoagulatio

Profiling of warfarin pharmacokinetics‐associated genetic variants: Black Africans portray unique genetic markers important for an African specific warfarin pharmacogenetics‐dosing algorithm

Background: Warfarin dose variability observed in patients is attributed to variation in genes involved in the warfarin metabolic pathway. Genetic variation in CYP2C9 and VKORC1 has been the traditional focus in evaluating warfarin dose variability, with little focus on other genes. Objective: We set out to evaluate 27 single nucleotide polymorphisms (SNPs) in the CYP2C cluster loci and 8 genes (VKORC1, ABCB1, CYP2C9, CYP2C19, CYP2C8, CYP1A2, CYP3A4, and CYP3A5) involved in pharmacokinetics of warfarin. Patients/methods: 503 participants were recruited among black Africans and Mixed Ancestry population groups, from South Africa and Zimbabwe, and a blood sample taken for DNA. Clinical parameters were obtained from patient medical records, and these were correlated with genetic variation. Results: Among black Africans, the SNPs CYP2C rs12777823G>A, CYP2C9 c.449G>A (*8), CYP2C9 c.1003C>T (*11) and CYP2C8 c.805A>T (*2) were significantly associated with warfarin maintenance dose. Conversely, CYP2C9 c.430C>T (*2), CYP2C8 c.792C>G (*4) and VKORC1 g.-1639G>A were significantly associated with maintenance dose among the Mixed Ancestry. The presence of CYP2C8*2 and CYP3A5*6 alleles was associated with increased mean warfarin maintenance dose, whereas CYP2C9*8 allele was associated with reduced warfarin maintenance dose. Conclusion: African populations present with a diversity of variants that are important in predicting pharmacogenetics-based warfarin dosing in addition to those reported in CYP2C9 and VKORC1. It is therefore important, to include African populations in pharmacogenomics studies to be able to identify all possible biomarkers that are potential predictors for drug response

Clinical characteristics and initial management of patients with tuberculous pericarditis in the HIV era: the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry

BACKGROUND: The incidence of tuberculous pericarditis has increased in Africa as a result of the human immunodeficiency virus (HIV) epidemic. However, the effect of HIV co-infection on clinical features and prognosis in tuberculous pericarditis is not well characterised. We have used baseline data of the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry to assess the impact of HIV co-infection on clinical presentation, diagnostic evaluation, and treatment of patients with suspected tuberculous pericarditis in sub-Saharan Africa. METHODS: Consecutive adult patients in 15 hospitals in three countries in sub-Saharan Africa were recruited on commencement of treatment for tuberculous pericarditis, following informed consent. We recorded demographic, clinical, diagnostic and therapeutic information at baseline, and have used the chi-square test and analysis of variance to assess probabilities of significant differences (in these variables) between groups defined by HIV status. RESULTS: A total of 185 patients were enrolled from 01 March 2004 to 31 October 2004, 147 (79.5%) of whom had effusive, 28 (15.1%) effusive-constrictive, and 10 (5.4%) constrictive or acute dry pericarditis. Seventy-four (40%) had clinical features of HIV infection. Patients with clinical HIV disease were more likely to present with dyspnoea (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.4 to 7.4, P = 0.005) and electrocardiographic features of myopericarditis (OR 2.8, 95% CI 1.1 to 6.9, P = 0.03). In addition to electrocardiographic features of myopericarditis, a positive HIV serological status was associated with greater cardiomegaly (OR 3.89, 95% CI 1.34 to 11.32, P = 0.01) and haemodynamic instability (OR 9.68, 95% CI 2.09 to 44.80, P = 0.0008). However, stage of pericardial disease at diagnosis and use of diagnostic tests were not related to clinical HIV status. Similar results were obtained for serological HIV status. Most patients were treated on clinical grounds, with microbiological evidence of tuberculosis obtained in only 13 (7.0%) patients. Adjunctive corticosteroids were used in 109 (58.9%) patients, with patients having clinical HIV disease less likely to be put on them (OR 0.37, 95% CI 0.20 to 0.68). Seven patients were on antiretroviral drugs. CONCLUSION: Patients with suspected tuberculous pericarditis and HIV infection in Africa have greater evidence of myopericarditis, dyspnoea, and haemodynamic instability. These findings, if confirmed in other studies, may suggest more intensive management of the cardiac disease is warranted in patients with HIV-associated pericardial disease

Mortality in patients treated for tuberculous pericarditis in sub-Saharan Africa.

Tuberculous pericarditis is one of the most severe forms of extrapulmonary tuberculosis, causing death or disability in a substantial proportion of affected people.1,2 In Africa, the incidence of tuberculous pericarditis is rising as a result of the HIV epidemic.3 The effect of HIV infection on survival in patients with tuberculous pericarditis is unknown.2,4 Whereas some investigators have suggested that HIV-infected patients with tuberculous pericarditis have a similar outcome to non-infected cases,5 others have shown that there may be an increase in mortality in HIV associated with tuberculous pericarditis.2,6,7 We established a prospective observational study, the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry, to obtain current information on the diagnosis, management and outcome of patients with presumed tuberculous pericarditis living in sub-Saharan Africa, where the burden of HIV infection is the greatest in the world.4,8-10 In this paper, we report the mortality rate and its predictors during the 6 months of antituberculosis treatment among patients enrolled in the regis

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Optimum INR intensity and therapeutic INR control in patients with mechanical heart valve prosthesis on warfarin oral anticoagulation at Dr George Mukhari academic hospital: a three-year retrospective study

Background: Available evidence suggest that the optimum prothrombin time-international normalised ratio (PT-INR) intensities recommended for anticoagulation of patients with mechanical heart valve prosthesis may not apply to all race groups. Optimal PT-INR target ranges and effectiveness of warfarin oral anticoagulation were determined among black South African patients fitted with St Jude bileaflet mechanical heart valve prosthesis (SJBMHVP) at Dr George Mukhari Academic Hospital (DGMAH). Methods: A convenience sample of 95 medical records of patients fitted with SJBMHVP from 1994 until 2013 was reviewed. Optimum PT-INR target ranges were estimated using two different methods: the classical two PT-INR target level method and the alternative, PT-INR specific incident rate method. The quality of warfarin anticoagulation was assessed using the fraction in therapeutic range method.Results: Optimum PT-INR target ranges for all participants fitted with SJBMHVP in the aortic position was estimated to be 2.0–3.5 and 2.6–3.5, respectively, by the classical and alternative methods. That of the patients with mitral valve replacement was estimated to be in the range 2.6–3.5 by the classical method and that of patients with double heart valve replacement was estimated to be 3.5 by both methods. The quality of warfarin anticoagulation of participants with SJBMHVP replacement was found to be inadequate as indicated by percentage time in treatment range (TTR) of 49.7% for all study participants compared with the ideal TTR of 70% and above.Conclusion: Optimum Caucasian-based PT-INR intensities recommended for oral anticoagulation of patients fitted with mechanical heart valve prosthesis are applicable to black patients fitted with SJBMHVP at DGMAH

Mortality in patients treated for tuberculous pericarditis in Sub-Saharan Africa

BibliographyObjective. To determine the mortality rate and its predictors in patients with a presumptive diagnosis of tuberculous pericarditis in sub-Saharan Africa. Design. Between 1 March 2004 and 31 October 2004, we enrolled 185 consecutive patients with presumed tuberculous pericarditis from 15 referral hospitals in Cameroon, Nigeria and South Africa, and observed them during the 6-month course of antituberculosis treatment for the major outcome of mortality. This was an observational study, with the diagnosis and management of each patient left at the discretion of the attending physician. Using Cox regression, we have assessed the effect of clinical and therapeutic characteristics (recorded at baseline) on mortality during follow-up. Results. We obtained the vital status of 174 (94%) patients (median age 33; range 14-87 years). The overall mortality rate was 26%. Mortality was higher in patients who had clinical features of HIV infection than in those who did not (40% v. 17%, p=0.001). Independent predictors of death during follow-up were: (i) a proven non-tuberculosis final diagnosis (hazard ratio (HR) 5.35, 95% confidence interval (CI) 1.76-16.25), (ii) the presence of clinical signs of HIV infection (HR 2.28, CI 1.14-4.56), (iii) coexistent pulmonary tuberculosis (HR 2.33, CI 1.20-4.54), and (iv) older age (HR 1.02, CI 1.01-1.05). There was also a trend towards an increase in death rate in patients with haemodynamic instability (HR 1.80, CI 0.90-3.58) and a decrease in those who underwent pericardiocentesis (HR 0.34, CI 0.10-1.19). Conclusion. A presumptive diagnosis of tuberculous pericarditis is associated with a high mortality in sub-Saharan Africa. Attention to rapid aetiological diagnosis of pericardial effusion and treatment of concomitant HIV infection may reduce the high mortality associated with the disease.The IMPI Africa Registry was sponsored by the South African Medical Research Council and National Research Foundation (through the 2004 - 2006 Africa Fellowship to Dr C S Wiysonge); the University of Cape Town’s Cardiac Clinic Research Fund; and the MESAB (Medical Education for South African Blacks) (through the 2003 Don Kennedy Scholarship to Dr M Ntsekhe)