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Results:

A total of 1212 patients were randomly assigned to medical therapy alone (602 patients) or medical therapy plus CABG (61 0 patients). By the end of the follow-up period. 1 00 patients in the medical-therapy group (17%) underwent CABG, and 555 patients in the CABG group (91%) underwent CABG.

Primary ou1come (CABG vs medical therapy alone) Rate of death from any cause Hazards Ratio (HR) 0.86 (0.72-1.04) P= 0.12

Secondary outcomes (CABG vs medical therapy alone) Death from any cause within 30 days after randomization HR 3.1 2 (1.33-7.31) P=0.006 Death from cardiovascular causes HR 0.81 (0.66-1.00) P=0.05 Death from any cause or hospitalization for heart failure HR 0.84 (0.71-0.98) P=0.03 Death from any cause or hospitalization for cardiovascular causes HR 0.74 (0.64-0.85) P

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The drug ad is focused on Efrenzia, a novel anti-platelet agent for the treatment of acute coronary syndromes.

Item 1 of2

A 58-year-old man with a history of hypertension and type 2 diabetes mellitus comes to the emergency department because of chest pain and diaphoresis. The symptoms started two hours ago and have a stuttering course. He has never had similar symptoms before. In the emergency department, his electrocardiogram shows horizontal ST segment depression in leads V1 to V4. He is given the appropriate medical therapy including low-dose aspirin, and referred to the catheterization laboratory due to persistence of his angina. Based on the information provided in the drug ad, giving the patient Efrenzia as opposed to clopidogrel would most likely decrease the risk of developing which of the following subsequent events?

View Drug Ad

r A. Cardiovascular death [21%] r B. Major bleeding [6%] r C. Non-fatal stroke [14%]

., r D. Recurrent myocardial infarction [59%]

Explanation: User ld:

This drug ad is comparing the effect of administering Efrenzia vs. clopidogrel in combination with aspirin for patients with acute coronary syndrome undergoing percutaneous coronary intervention, including those with unstable angina (UA)/non-ST elevation myocardial infarction (NSTEMI) and ST-elevation Ml (STEMI). The results are reported as the percentage of patients developing a composite endpoint of cardiovascular death, non-fatal Ml, or nonfatal stroke over the subsequent 18 months. A subgroup analysis was also performed in diabetics presenting with NSTEM/UA or STEML

There was a 2. 7% overall decrease of events in patients with STEM I ( 12.4% reduced to 9. 7%) and a 1 .8% decrease of events in UAINSTEMI patients ( 1 0. 7% reduced to 8.9%). The text under the section titled "Benefit in STEMI and UAINSTEMI patients" indicates that the reason for the difference between the treatments was primary due to a significant reduction in (recurrent) non-fatal Mls.

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Item: 12 of 44 11 PM ark -- j f ~ ~~ I Q.ld: 3947 [ Previous Ne>VSMLEW11tHL<

Effect modification results when an external variable positively or negatively impacts the effect of a risk factor on the disease of interest. It can sometimes be confused with confounding. the bias that results when the exposure-disease relationship is obscured by the effect of an extraneous factor that is associated with both the exposure and disease. Effect modification can be distinguished from confounding by performing a stratified analysis centering on the variable of interest. If the variable is a confounder. there will be no significant difference in risk between the stratified groups as the confounding effects are now removed. However. if the variable is instead an effect modifier. there will be a significant difference between the 2 groups.

In this case. stratification by family history shows that oral contraceptives significantly increase the risk of breast cancer in patients with a positive family history but not in patients with a negative family history. Thus. family history is not a confounding variable (Choice A). Rather. positive family history acts as an effect modifier to increase the risk of breast cancer in patients taking oral contraceptives. Other well-known examples of effect modification include the effect of estrogens on the risk of venous thrombosis (augmented by smoking) and the risk of lung cancer in people exposed to asbestos (also enhanced by smoking).

(Choice C) The latency period is the time required for a given exposure to have a measurable effect on the outcome. This study provided no information on how long oral contraceptives must be used in order to have an effect on breast cancer risk in susceptible patients.

(Choices D and E) Flaws in a study involving subject enrollment or data recording can result in selection bias or observer bias. respectively. Effect modification is not a bias. but rather a natural phenomenon that is importantto recognize.

Educational objective: Effect modification results when an external variable positively or negatively impacts the effect of a risk factor on the disease of interest. It can be distinguished from confounding by performing a stratified analysis centered on the variable of interest. Effect modification is not a bias. but rather is a natural phenomenon that is important to recognize.

Time Spent 1 seconds Copyright USMLEWorld .LLC. Last updated [7/12/20 13]

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Item: 16 of 44 11 PM ark -- j f "" 1.":~ I Q.ld: 3931 [ Previous Ne> were ranaom1y se1ecrea rrom the same population where the patients came from. and asked abouttheir experience with L-tryptophan containing products within the last 6 months. The study showed that the use of L-tryptophan is significantly associated with EMS. Which of the following measures of association are the investigators most likely to report?

r A. Relative risk [27%] r B. Median survival [1 %]

., r C. Exposure odds ratio [63%] r D. Relative rate [3%] r E. Prevalence odds ratio [5%]

Explanation: User ld:

The above case describes a typical case-control study design. Patients with the disease of interest (cases) and people without the disease (controls) are asked about previous exposure to the variable being studied (L-tryptophan use). The main measure of association is the exposure odds ratio. in which the exposure of people with the disease (cases) is compared to the exposure of those without the disease (controls).

(Choices A and D) Incidence measures (e.g .. relative risk or relative rate) cannot be directly measured in case-control studies because the people being studied are those who have already developed the disease. Relative risk and relative rate are calculated in cohort studies. where people are followed over time for the occurrence of the disease.

(Choice B) Median survival is calculated in cohort studies or clinical trials. and is usually used to compare the median survival times in two or more groups of patients (e.g .. receiving a new treatment or placebo).

(Choice E) Prevalence odds ratio is calculated in cross-sectional studies to compare the prevalence of a disease between different populations.

Educational Objective: A case-control study is used to compare the exposure of people with the disease (cases) to the exposure of the people without the disease (controls). The main measure of association is the exposure odds ratio.

Time Spent 2 seconds Copyright USMLEWorld .LLC. Last updated [7/7/20 1 0]

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Item: 18 of 44 !II PM ark - j f ~ 1.":~ I Q.ld: 7686 [ Previous Ne> 1 signifies that an event is more likely to occur in the treatment arm. A ratio close to 1 implies little difference between the two groups. In this study. the hazard ratio for major bleeding was 0.96 (given in the bleeding statistics under the chart). which is the closest to 1 compared to the other answer options. Additionally. the 95% confidence interval (0 .84 - 1 .1 D) contains the null value of 1 . indicating that there is no significant difference in the risk of major bleeding between the 2 groups.

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Item: 18 of 44 11 PM ark - j f 9- 1.":~ I Q.ld: 7686 [ Previous Ne> 1 signifies that an event is more likely to occur in the treatment arm. A ratio close to 1 implies little difference between the two groups. In this study. the hazard ratio for major bleeding was 0.96 (given in the bleeding statistics under the chart). which is the closestto 1 compared to the other answer options. Additionally. the 95% confidence interval (0 .84 - 1 .1 D) contains the null value of 1 . indicating thatthere is no significant difference in the risk of major bleeding between the 2 groups.

(Choice A) The hazard ratio for intracranial bleeding is 0.39. indicating that Kalaxin has a lower chance of causing intracranial bleeding than warfarin.

(Choice B) The hazard ratio for gastrointestinal (GI) bleeding is 1 75. indicating that Kalaxin has a higher chance of causing gastrointestinal bleeding than warfarin. The hazard ratio for major Gl bleeding is 1 .38.

(Choice C) The hazard ratio for life-threatening bleeding is 0.75. indicating that Kalaxin has a lower chance of causing life-threatening bleeding than warfarin.

(Choice E) The hazard ratio for total bleeding is 0.91 . indicating that Kalaxin has a slightly lower chance of causing overall bleeding than warfarin.

Educational objective: Hazard ratios are proportions that indicate the chance of an event occurring in the treatment arm as compared to the chance of the event occurring in the control arm.

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A gynecologic oncology research institute isolates a potential tumor marker for endometrial cancer. A large multicenter study is then performed to evaluate serum levels of the tumor marker in women with and without endometrial cancer. The following curves are generated using the results of the study.

Ill ....

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Results.

1979 patients (233 regular users of low-dose aspirin and 17 46 who never used low-dose aspirin) were studied. Advanced neoplasms were found in 24 users ( 1 0.3%) and 181 nonusers ( 1 0 A%) of low-dose aspirin.

Figure 3 . Receiver Operating Characteristic Curves for Detecting Advanced Colorectal Neoplasms by Quanti tative lmmunochemical Fecal Occult B lood Test According to Use of Low-Dose Aspi r in

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p g ( ) p positive rate (sensitivity) againstthe false positive rate ( 1 -specificity. or inverse true negative rate). at different cutoff points for a given diagnostic test. This curve usually shows that an increase in sensitivity is offset by a decrease in specificity.

The figure above shows the ideal diagnostic test ( 1 DO % sensitive and specific). which provides the most useful information. A diagnostic test that provides no useful information usually produces the diagnosis by random chance and demonstrates an inverse linear relationship between sensitivity and specificity.

100 80 60 40 20 Specificity (%)

~ Accuracv is defined as the proportion of true results (true

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F1gure 3 . Rece1ver Operating Charactenst1c Curves for Detecting Advanced Colorectal Neoplasms by Quantitative lmmunochemical Fecal Occult Blood Test According to Use of Low-Dose Aspirin

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Accuracy is defined as the proportion of true results (true positive and true negative) out of all the results that are predicted by a test in a given population. as measured by a gold standard or reference parameter. The closer the plotted curve approaches the left and top borders of the ROC curve. the more accurate the test is. Accuracy can also be measured as the total area under the plotted curve. Precision is defined as the proportion of true positives out of the total number of positive results produced by a test in a given population. Precision is equivalent to positive predictive value. Both accuracy and precision depend upon the sensitivity and specificity of the test. as well as the prevalence of the condition in the population being tested .

In this study, aspirin use moves the ROC curve upwards. This translates to an increase in sensitivity(Choice 8). However, the curve also shifts to the right for a given cutoff point with aspirin use. indicating a decrease in the specificity (Choice D). The total area under the plotted curve increases with aspirin use (despite the decrease in specificity, as the magnitude increase in sensitivity is larger). leading to an increase in overall accuracy (Choice A) .

Educational objective: A shift in the ROC curve upwards for a given cutoff indicates increased sensitivity. A shift of the curve to the right for a given cutoff point indicates a decrease in specificity.

Time Spent 40 .:::J seconds

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Cut points, 1-fg/9 stool Users of low-dose aspirin o Nonusers of low-dose aspirin

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Conclusion:

For two iF OBTs, low-dose aspirin use affects performance of the test in detecting advanced colorectal neoplasm.

Funding Source: the German Research Foundation, the German Federal Ministry of Education and Research. The test kits were provided free of charge by the manufacturer.

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Accuracy is defined as the proportion of true results (true positive and true negative) out of all the results that are predicted by a test in a given population, as measured by a gold standard or reference parameter. The closer the plotted curve approaches the left and top borders of the ROC curve, the more accurate the test is. Accuracy can also be measured as the total area under the plotted curve. Precision is defined as the proportion of true positives out of the total number of positive results produced by a test in a given population. Precision is equivalentto positive predictive value. Both accuracy and precision depend upon the sensitivity and specificity of the test, as well as the prevalence of the condition in the population being tested.

In this study, aspirin use moves the ROC curve upwards. This translates to an increase in sensitivity(Choice B). However, the curve also shifts to the right for a given cutoff point with aspirin use, indicating a decrease in the specificity (Choice D). The total area under the plotted curve increases with aspirin use (despite the decrease in specificity, as the magnitude increase in sensitivity is larger), leading to an increase in overall accuracy (Choice A).

Educational objective: A shift in the ROC curve upwards for a given cutoff indicates increased sensitivity. A shift of the curve to the right for a given cutoff point indicates a decrease in specificity.

Time Spent 40 ~ seconds

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Results.


Figure 3. Receiver Operating Characteristic Curves for Detecting Advanced Colorectal Neoplasms by Quanti tative lmmunochemical Fecal Occult B lood Test According to Use of Low-Dose Aspi r in

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Positive Negative condition condition

Positive Test True positive False positive result (TP) (FP)

Negative Test False negative True negative result (FN) (TN)

Sensitivity = TP I (TP+FN) Specificity = TN I (TN+FP)

PPV = TP I (TP+FP) NPV = TNI(TN+FN)

The equations for PPV and NPV are defined above, along with the ones for sensitivity and specificity. As the sensitivity increases, the NPV increases (due to fewer FN). As the specificity increases, the PPV increases (due to lower FP). It is important to note that while sensitivity and specificity depend only upon the characteristics of a given test, PPV and NPV also depend upon the prevalence of the condition in the population being tested. PPV varies directly with prevalence (higher prevalence correlates with higher PPV), while NPV varies inversely with prevalence (higher prevalence corresponds with lower NPV).

The Receiver Operating Characteristic (ROC) curve in the studies above show that an increase in the cutoff value from 1 ~gig to 4 ~gig decreased the sensitivity of the hemoglobin test from 70% to 60% and increased the specificity from 80% to 90%. Similarly, the hemoglobin-haptoglobin test also had a decrease in sensitivity from 60% to 40% and an increase in specificity from 80% to 90% with the same increase in cutoff values. This increase in specificity correlates with an increase in the PPV .

~ (Choice A) NPV would increase following an increase in

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Results.


Figure 3 . Receiver Operating Characteristic Curves for Detecting Advanced Colorectal Neoplasms by Quanti tative lmmunochemical Fecal Occult B lood Test According to Use of Low-Dose Aspirin

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0

y p g ' depend upon the prevalence of the condition in the population being tested. PPV varies directly with prevalence (higher prevalence correlates with higher PPV), while NPV varies inversely with prevalence (higher prevalence corresponds with lower NPV).

The Receiver Operating Characteristic (ROC) curve in the studies above show that an increase in the cutoff value from 1 ~gig to 4 ~gig decreased the sensitivity of the hemoglobin test from 70% to 60% and increased the specificity from 80% to 90%. Similarly, the hemoglobin-haptoglobin test also had a decrease in sensitivity from 60% to 40% and an increase in specificity from 80% to 90% with the same increase in cutoff values. This increase in specificity correlates with an increase in the PPV.

(Choice A) NPV would increase following an increase in sensitivity. This example demonstrated a decrease in sensitivity, which would lead to a corresponding decrease in the NPV.

(Choices B and D) The number of false positives would decrease if the cutoff rate were increased, since it would be harder to obtain a positive test result. This would also lead to decreased sensitivity since the number of false negatives increases .

Educational objective: Changing the cutoff value of a test for a given condition alters the PPV, NPV, sensitivity, and specificity. Increased specificity correlates with increased PPV and increased sensitivity corresponds to increased NPV. PPV and NPV also depend upon the condition's prevalence .



Last updated: [2111120 13]

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Item: 27 of 44 !il PM ark j f ~ ~ I Q.ld: 7688 [ Previous Ne> 50 mUmin/1.73 m2 9.07 (3.18-25.88)

Follow-uo GFR > 30 to_;;s40 vs 3.6711 .21-11.15\

p Value

.006

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Follow-up GFR > 40 to :s50 vs 1.98 (0.59-6.61) .27 > 50 mUmin/1.73 mz

Follow-up UP/Cr > 0.08 to :s0.22 2.01 (0.92-4.39) .08 vs !50.08

Follow-up UP/Cr >0.22 to :s0.66 1.50 (0.62-3.63) .37 vs !50.08

Followup UP/Cr > 0.66 vs :s0.08 1.84 (0.78-4.30) .16 followup potassium level4-5 7.25 (1.7230.58) .007

vs < 4 mEq/L Follow-up potassium level > 5 30.83 (6.89-138.0) < .001

vs < 4 mEq/L

Conclusion:

In non-diabetic patients with hypertensive CKD treated with ACEis. the risk of hyperkalemia is small.

Funding Source: The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant; additional financial support from the Office of Research in Minority Health and drug donations from Pfizer Inc. AstraZeneca Pharmaceuticals. and King Pharmaceuticals.

Structured abstract is based on: Arch Intern Med. 2009; 169( 17) 1587-94

(Choice B) The hazard ratio for follow-up use of a diuretic was 0 A 1 (with a statistically significant p value 30 and ~40 according to the figure above. so discontinuation of the drug likely would not have a significant effect on the potassium.

(Choice E) Fallow-up UP/Cr of 1 .1 as compared to baseline has a hazard ratio of 1 .84. indicating that there is an increased incidence of hyperkalemia. However. this ratio is lower than the hazard ratio for follow-up potassium level between 4-5 mEq/L and it is not statistically significant (p=O .16).

Educational objective: Hazard ratios are the ratio of an event rate occurring in the treatment arm versus the non-treatment arm. Ratios less than 1 indicate that the treatment arm had a lower event rate while ratios higher than one indicate the treatment arm had a higher rate of events.

References:

1 . Biostatistics primer: what a clinician ought to know: hazard ratios.

2. Estimation of the 2 -sample hazard ratio function using a semi parametric model.


Copyright USMLEWorld .LLC.


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Item: 28 of 44 I ' Mak j f ~ l~:'ll O.ld: 7689 ( Prevous NeHt Lab Values Notes Calculato1

Risk of Hyperkalemia In Non-diabetic Patients with Chronic Kidney Disease Receiving Antihypertensive Therapy

Objective:

Explore the incidence and factors associated with hyperkalemia in patients with chronic kidney disease (CKD) treated with antihypertensive drugs

Methods:

Design: Randomized clinical trial

Blinding: Double-blinded

Follow-up: 3 to 6.4 years

Selling: Multicenter (21 medical centers)

Patients: African American patients . aged 18 to 70 years. with hypertensive CKD as defined by a diastolic blood pressure (BP) higher than 95 mm Hg and a glomerular filtration rate (GFR) between 20 and 65 mUmin/1.73 m2. Specific exclusion criteria included diabetes mellitus: urinary protein to urinary creatinine ratio (UP/Cr) higher than 2.5: accelerated or malignant hypertension: secondary hypertension: serious systemic disease: congestive heart failure: and initial potassium level higher than 5.5 mEq/L

Intervention: Patients were randomized to initial treatment with either a beta-blocker (metoprolol), an ACE inhibitor (ramipril), or a calcium channel blocker (amlodipine) and to 1 of 2 mean arterial BP goals (1 02- 107 mmHg or

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A total of 1 094 non-diabetic patients were randomized. A total of 6497 potassium measurements were obtained, and 80 hyperkalemic events in 51 subjects were identified.

~ 15 RaMomlzed Oruo Groop l!i 0 Rarniprll

~ 12 0 Metroprol succinate AmiOPidine besylale E "' &'! 9 0 s;!

6 ~ .!l "' 3 a: E ~ w 0

Figure 1. Hyperkalemia event rate per 100 patientyears by randomized drug groups and baseline glomerular filtration rate (GFR). Error bars indicated 95% confidence intervals.

Table 4. Association of Risk of Hyperkalemia With Time-Dependent Factors In Mulllvariable Analysls3

Hazard Ratio (95% Confidence p

Variable Interval) Value

Follow-up diuretic use 0.41 (0.22-0.78) .006 Followup GFR s 30 vs

> 50 mUmin/1.73 m2 9.07 (3.18-25.88) 30 to :s40 vs 3.67 (1.21-1 1.15) .02 > 50 mUmln/1.73 mz

Follow-up GFR > 40 to s so vs 1.98 (0.596.61) .27

addition, the drugs also had 2 different blood pressure end points rather than one common end point to see what effect they also had on blood pressure.

(Choice A) Cluster analysis is the grouping of different data point into similar categories, which is not employed in this study. Cluster analysis usually involves randomization at the level of groups rather than at the level of individuals.

(Choice B) A cross-over study is one in which group of participants is randomized to one treatment for a period of time and the other group is given an alternate treatment for the same period of time. At the end of the time period, the two groups then switch treatments for another set period of time . This study gave the same treatment to the patients for the duration of the trial.

(Choice D) A parallel study randomizes one treatment to one group and a different treatment to the other group, such as treatment drug to one group versus placebo to the other group. There are usually no other variables measured, such as the two blood pressure goals in this study.

Educational objective: Factorial design studies involve randomization to different interventions with additional study of 2 or more variables.

References:

1. Design of experiments with multiple independent variables: a resource management perspective on complete and reduced factorial designs.




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Item: 36 of 44 !il PM ark j f ~ !:':~ I Q.ld: 2138 [ Previous Next Lab Values Notes Calculator

Researchers at a large pharmaceutical company discover a tumor-specific antigen present in high quantities in the serum of patients with pancreatic cancer. A study is then performed to evaluate serum levels of the tumor marker in patients with and withoutthe disease. The following curves are generated using the results of the study.

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Item: 42 of 44 !il PM ark I I ~ 1.":~ I Q.ld: 3909 [ Previous Ne> 1 .0 means that the outcome occurs more frequently in the exposed group (positive association). The RR says nothing about the statistical significance of a study.

Statistical significance can be expressed with either p values or confidence intervals. but both are interrelated. For instance. p < 0.05 corresponds to a 95% confidence interval that does not contain the null value. Likewise p < 0.01 is equivalent to a 99% confidence interval that does not contain the null value. Conversely. if the null value is within a given confidence interval. then the p value is~ the equivalent confidence interval.

Null value outside

confidence intervals

95% confidence

interval

p

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