2 Minute Medicine Rewind July 22, 2019

Association of Immune Marker Changes With Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma

Multiple myeloma often develops from the precursor condition monoclonal gammopathy of undetermined significance (MGUS), which is detectable in peripheral blood. Similarly, the light-chain subtype of multiple myeloma is preceded by light-chain MGUS. Clinical guidelines recommend annual peripheral blood monitoring of serum immune markers for patients with intermediate-risk and high-risk MGUS as determined by risk models that incorporate data from a single time-point. Longitudinal studies on serum immune markers in individuals with myeloma precursor disease to assess risk of disease progression have not been performed. In this prospective cross-sectional cohort study, 685 individuals with progressing or stable MGUS were studied to determine if longitudinal changes in serum immune markers are associated with progression from MGUS to multiple myeloma. The study was conducted from November 1993 through December 2011. Immune markers measured included serum protein and monoclonal immunoglobulin levels, serum free light chains, and serum light chains within each immunoglobulin class. During the 16-year follow-up period, 187 individuals progressed from MGUS to multiple myeloma or from light-chain MGUS to light-chain multiple myeloma. Researchers found that risk factors associated with progression of non-IgM MGUS to multiple myeloma were IgA isotype (OR 1.80, 95% CI 1.03 to 3.13, p=0.04), a monoclonal spike of 15 g/L or more (OR 23.5; 95% CI 8.9 to 61.9, p<0.001), a skewed (<0.1 or >10) serum free light chains ratio (OR 46.4, 95% CI 18.4 to 117.0, p<0.001), and severe immunoparesis (defined as two suppressed, uninvolved immunoglobulins; OR 19.1, 95% Cl 7.5 to 48.3; p<0.001). Risk factors associated with progression of light-chain MGUS to multiple myeloma were skewed serum free light chains ratio (OR 44.0, 95% CI 14.2 to 136.3 p<0.001) and severe immunoparesis (OR, 48.6, 95% CI, 9.5 to 248.2, p<0.001). Based on these identified risk factors, researchers calculated clinical risk scores and plotted them against longitudinal progression to multiple myeloma in individuals with at least one pre-diagnostic serum sample within two years of diagnosis and at least three serial samples. These analyses revealed that 53% of patients with MGUS that progressed to multiple myeloma had a high-risk score before progression, and 70% of these patients had preceding blood samples with low-risk and/or intermediate-risk scores. Similar results were found for light-chain MGUS. Overall, this study identified serum immune markers associated with progression from MGUS to multiple myeloma, and shows that low- or intermediate-risk MGUS can convert to high-risk MGUS, supporting the practice of annual serum immune marker testing in patients with MGUS or light-chain MGUS to determine clinical risk status.

The state of hypertension care in 44 low-income and middle-income countries: a cross-sectional study of nationally representative individual-level data from 1·1 million adults

The prevalence of hypertension is rapidly increasing in low-income and middle-income countries (LMICs). To effectively target interventions and monitor progress in hypertension care, it is essential to determine country-specific deficiencies in the hypertension care continuum. However, estimates of health system performance in hypertension care from nationally representative studies in LMICs are sparse. In this cross-sectional study, 192,441 patients with hypertension from 44 LMICs were evaluated to determine at which stages in the hypertension care cascade patients are lost, and how these losses vary between and within countries. Hypertension was defined as a systolic blood pressure of at least 140 mm Hg, a diastolic blood pressure of at least 90 mm Hg, or reported use of medication for hypertension. Researchers analyzed the hypertension cascade of care by computing the proportion of individuals who 1) had ever had their blood pressure measured, 2) had been diagnosed with hypertension, 3) had been treated for hypertension, and 4) had achieved control of their hypertension. Researchers found that 73.6% of patients (95% CI 72.9% to 74.3%) had ever had their blood pressure measured, 39.2% (95% CI 38.2% to 40.3%) had been diagnosed with hypertension, 29.9% (95% CI 28.6% to 31.3%) received treatment for hypertension, and 10.3% (95% CI 9.6% to 11.0%) achieved control of their hypertension. Countries in Latin America and the Caribbean had the highest proportion of individuals reaching each stage of the hypertension care cascade, whereas sub-Saharan Africa had the lowest proportion. Bangladesh, Brazil, Costa Rica, Ecuador, Kyrgyzstan, and Peru all performed significantly better on all care cascade steps than predicted based on GDP per capita. Individuals who were female, older, did not currently smoke, and who were in higher quintiles for household wealth were more likely to reach each step of the hypertension care cascade. Additionally, being overweight or obese was associated with a higher probability of reaching each cascade step in all regressions except for the last step, from treatment to control of blood pressure. This study was limited by differences in how survey questions were translated into local languages and in how blood pressure was measured, which may have been responsible for some of the variation observed between countries and regions. Overall, this study underlines the fact that targeted interventions to improve hypertension care in LMICs are urgently needed, and identifies specific areas for opportunity in the hypertension care cascade in 44 different countries.

Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial

Plasmodium vivax (P. vivax) malaria is a major cause of morbidity and mortality throughout the world. Primaquine, an 8-aminoquinoline, is the only widely available drug that prevents relapse, but its use is limited by the risk of acute hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency in addition to poor awareness of the benefits of primaquine in preventing relapsing infections in high-transmission areas. Moreover, when it is prescribed, poor adherence is common due to its lengthy 14-day regimen. Shorter courses with higher daily doses have been hypothesized to improve adherence, and thus effectiveness, without reducing efficacy; however, randomized controlled trials assessing a shorter course have not been done. In this randomized, double-blind, non-inferiority trial, 2,336 patients with uncomplicated P. vivax malaria and normal G6PD as assessed by the fluorescent spot test were given standard blood schizontocidal treatment and then assigned in a 2:2:1 ratio to receive 7 days of supervised primaquine (1.0 mg/kg per day), 14 days of supervised primaquine (0.5 mg/kg per day), or placebo. The primary outcome was the incidence rate of symptomatic P. vivax parasitemia during the 1-year follow-up period, assessed in the intention-to-treat population. A margin of 0.07 recurrences per person-year was used to establish non-inferiority of the 7-day regimen compared with the 14-day regimen. Researchers found no difference in the incidence rate of symptomatic recurrent P. vivax malaria between the 7-day and 14-day primaquine regimens (7-day regimen: 0.18 recurrences per person-year, 95% CI 0.15 to 0.21; 14-day regimen: 0.16, 95% CI 0.13 to 0.18; between-group difference 0.02, 95% CI -0.02 to 0.05, p=0.3405). Potentially drug-related serious adverse events within 42 days of starting treatment were slightly more frequent in the 7-day group (9 total events (1.0%) in the 7-day group vs. 1 event (0.1%) in the 14-day group). In conclusion, results from this study support the use of a 7-day course of primaquine for P. vivax in patients in whom G6PD deficiency can be definitively ruled out.

The clinical and cost-effectiveness of total versus partial knee replacement in patients with medial compartment osteoarthritis (TOPKAT): 5-year outcomes of a randomised controlled trial

The two main surgical options for late-stage medial compartment osteoarthritis of the knee are partial knee replacement (PKR) and total knee replacement (TKR). There is significant variation in choice of approach among surgeons, likely because randomized controlled trials comparing the two approaches have not been performed. In this multicenter, randomized controlled trial, 528 patients with isolated osteoarthritis of the medial compartment of the knee were assigned to PKR or TKR to compare the clinical effectiveness of the two procedures measured by the Oxford Knee Score (OKS) 5 years after randomization. The OKS is a patient self-reported outcome questionnaire that was specifically developed to assess function and pain after knee replacement surgery. Health-care costs and cost-effectiveness were also assessed. Researchers found no difference in OKS between the two study groups at 5 years (mean difference 1.04, 95% CI -0.42 to 2.50; p=0.159). Moreover, there was no difference in patient satisfaction between the two groups at 5 years (82% satisfied with knee in PKR group vs. 77% in TKR group, RR 1.06, 95% CI 0.99 to 1.13, p=0.097). Patients receiving TKR had more complications than those receiving PKR (27% vs. 20%, respectively, RR 0.72, 95% CI 0.53 to 0.98; p=0.036). Finally, researchers found that PKR was more effective (0.240 additional QALYs as compared to TKR, 95% CI 0.046 to 0.434) and less expensive (-910£, 95% CI -1503£ to -317£) than TKR during the 5 years of follow-up. Limitations of this study include the absence of masking and the fact that the number of participants who completed follow-up was slightly less than the target of 500 participants required to reach adequate power. In summary, this study indicates that both TKR and PKR offer similar clinical outcomes, but overall suggests that PKR should be considered the first choice for patients with late-stage isolated medial compartment osteoarthritis given its superior cost-effectiveness.

Effect of Simvastatin-Ezetimibe Compared With Simvastatin Monotherapy After Acute Coronary Syndrome Among Patients 75 Years or Older: A Secondary Analysis of a Randomized Clinical Trial

The risk of adverse cardiovascular outcomes in patients hospitalized with acute coronary syndrome (ACS) is highest in elderly patients. Although recent clinical trials have shown that high-intensity statin therapy significantly reduces adverse cardiovascular events for patients with established coronary heart disease, its use in elderly individuals remains controversial. As such, recent lipid treatment guidelines do not advocate for the routine use of high-intensity therapy for patients older than 75 years. In this pre-specified secondary analysis of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), outcomes were compared by age among 18,144 patients hospitalized for ACS and assigned to either simvastatin plus ezetimibe or simvastatin plus placebo. The primary endpoint was a composite of death due to a cardiovascular event, major adverse cardiac event (non-fatal MI, unstable angina leading to hospitalization, coronary revascularization after day 30), or nonfatal stroke. At randomization, 56.1% of patients were less than 65 years old, 28.5% were 65 to 74 years old, and 15.4% were 75 years or older. Researchers found that patients of all ages in the simvastatin-ezetimibe group had lower rates of the primary endpoint than those in the simvastatin-placebo group, with the greatest absolute risk reduction (8.7%) occurring in patients 75 years or older (less than 65 years of age: 29.9% vs. 30.8% respectively, absolute risk reduction 0.9%, HR 0.97, 95% CI 0.90 to 1.05; 65 to 74 years of age, 35.1% vs. 35.9% respectively, absolute risk reduction 0.8%, HR 0.96, 95% CI 0.87 to 1.0; 75 years of age or older: 38.9% vs. 47.6% respectively, absolute risk reduction 8.7%, HR 0.80, 95% CI 0.70 to 0.90). The number needed to treat to prevent one primary end point event by treatment with simvastatin-ezetimibe was 125 (95% CI 113 to infinity) among patients younger than 75 and 11 (95% CI 8 to 23) among patients 75 years or older. The rate of adverse events did not increase with age or with simvastatin-ezetimibe therapy as compared to simvastatin-placebo. In summary, this study suggests that the use of high-intensity therapy with simvastatin-ezetimibe to lower lipid levels in patients 75 years or older after ACS is well-tolerated and may improve clinical outcomes as compared to simvastatin monotherapy.

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