Testosterone Therapy and Risk of Acute Myocardial Infarction in Hypogonadal Men: An Administrative Health Care Claims Study.

BACKGROUND: There are some ongoing debates on the potential link between testosterone therapy (TT) and risk of acute myocardial infarction (MI). AIM: To investigate the association between acute MI and TT use compared with non-use in men having documented hypogonadism (diagnostic International Classification of Diseases, Ninth Revision codes 257.2, 257.8, 257.9, 758.7) in patient claims records. METHODS: This retrospective cohort study used a real-world US-based administrative health care claims database (MarketScan 2004-2013; Truven Health Analytics, Ann Arbor, MI, USA) to compare MI rates between TT-treated men and a cohort of untreated hypogonadal men matched by a calendar time-specific propensity score. Subgroup analyses were performed by route of administration, age, and prior cardiovascular disease (CVD). OUTCOMES: Incidence rates of MI (per 1,000 person-years) and hazard ratio. RESULTS: After 1:1 calendar time-specific propensity score matching, 207,176 TT-treated men and 207,176 untreated hypogonadal men were included in the analysis (mean age = 51.8 years). Incidence rates of MI were 4.20 (95% CI = 3.87-4.52) in the TT-treated cohort and 4.67 (95% CI = 4.43-4.90) in the untreated hypogonadal cohort. Cox regression model showed no significant association between TT use and MI when comparing TT-treated with untreated hypogonadal men overall (hazard ratio = 0.99, 95% CI = 0.89-1.09), by age, or by prior CVD. A significant association was observed when comparing a subgroup of injectable (short- and long-acting combined) TT users with untreated hypogonadal men (hazard ratio = 1.55, 95% CI = 1.24-1.93). CLINICAL IMPLICATION: In this study, there was no association between TT (overall) and risk of acute MI. STRENGTHS AND LIMITATIONS: Strengths included the use of a comprehensive real-world database, sophisticated matching based on calendar blocks of 6 months to decrease potential bias in this observational study, carefully chosen index dates for the untreated cohort to avoid immortal time bias, and implemented sensitivity analysis to further investigate the findings (stratification by administration route, age, and prior CVD). Key limitations included no information about adherence, hypogonadism condition based solely on diagnosis (no information on clinical symptoms or testosterone levels), lack of information on disease severity, inability to capture diagnoses, medical procedures, and medicine dispensing if corresponding billing codes were not generated and findings could contain biases or fail to generalize well to other populations. CONCLUSION: This large, retrospective, real-world observational study showed no significant association between TT use and acute MI when comparing TT-treated with untreated hypogonadal men overall, by age, or by prior CVD; the suggested association between injectable TT and acute MI deserves further investigation. Li H, Mitchell L, Zhang X, et al. Testosterone Therapy and Risk of Acute Myocardial Infarction in Hypogonadal Men: An Administrative Health Care Claims Study. J Sex Med 2017;14:1307-1317.

Impact of Testosterone Solution 2% on Ejaculatory Dysfunction in Hypogonadal Men.

INTRODUCTION: Hypogonadism is defined as decreased testosterone levels in men. Hypogonadism can be accompanied by erectile, orgasmic, and ejaculatory dysfunction. AIMS: To evaluate whether treatment with testosterone solution 2% (testosterone) could improve ejaculatory function in a cohort of hypogonadal men. METHODS: Sexually active, hypogonadal men at least 18 years old (total testosterone < 300 ng/dL) were randomized to receive testosterone or placebo for 12 weeks. MAIN OUTCOME MEASURES: Effects of testosterone on primary outcomes were evaluated using the International Index of Erectile Function (IIEF) and the Men's Sexual Health Questionnaire, Ejaculatory Dysfunction, Short Form (MSHQ-EjD-SF) questionnaires. Treatment differences were calculated using analysis of covariance. RESULTS: In total, 715 men (mean age = 55 years) were randomized to placebo (n = 357) or testosterone (n = 358). Most sexually active men who reported IIEF scores had some degree of erectile dysfunction (IIEF erectile function score < 26). Although ejaculatory function score (MSHQ-EjD-SF) improved in the testosterone group compared with placebo (P < .001), improvement on the "bother" item did not reach statistical significance. Treatment-related adverse events in the testosterone group affecting at least 1% of patients were increased hematocrit, upper respiratory tract infection, arthralgia, burning sensation, fatigue, increased prostate-specific antigen, erythema, and cough. Few patients in either treatment group developed at least one adverse event leading to discontinuation (testosterone = 1.98% vs placebo = 3.09%; P = .475). CONCLUSION: Hypogonadal men receiving testosterone solution 2% therapy experience significantly greater improvement in ejaculatory function, compared with placebo, as assessed by the MSHQ-EjD-SF. However, improvement in "bother" was not statistically different between the two groups. Testosterone therapy was generally well tolerated.

Demographic and Clinical Correlates of Patient-Reported Improvement in Sex Drive, Erectile Function, and Energy With Testosterone Solution 2.

INTRODUCTION: Evidence from well-designed studies documenting the benefit of testosterone replacement therapy as a function of patient demographic and clinical characteristics is lacking. AIM: To determine demographic and clinical predictors of treatment outcomes in hypogonadal men with low sex drive, low energy, and/or erectile dysfunction. METHODS: Post hoc analysis of a randomized, multicenter, double-blinded, placebo-controlled, 16-week study of 715 hypogonadal men (mean age = 55.3 years, age range = 19-92 years) presenting with low sex drive and/or low energy who received placebo or testosterone solution 2% for 12 weeks. MAIN OUTCOMES AND MEASURES: Two levels defined patient-reported improvement (PRI) in sex drive or energy: level 1 was at least "a little better" and level 2 was at least "much better" in energy or sex drive on the Patient Global Impression of Improvement at study end point. PRI in erectile function was stratified by erectile dysfunction severity at baseline as measured by the erectile function domain of the International Index for Erectile Function: mild at baseline (change of 2), moderate at baseline (change of 5), and severe at baseline (change of 7). Associations of demographic and clinical characteristics with PRI were calculated with stepwise forward multiple logistic regression analysis. Odds ratios represented the likelihood of PRI in symptoms among variable categories. RESULTS: Higher levels of end-point testosterone were associated with higher rates of PRI (at levels 1 and 2) in sex drive and energy (P < .001 for the two comparisons). Lower baseline testosterone levels were associated with higher rates of level 1 PRI in sex drive (P = .028); and classic hypogonadism (vs non-classic hypogonadism) was associated with higher rates of level 2 PRI in sex drive (P = .005) and energy (P = .006). CONCLUSION: When assessing the potential for improvements in men with testosterone deficiency using patient-reported outcome questionnaires, possible predictors of treatment outcomes to consider include the etiology of hypogonadism and testosterone levels (baseline and end point).

9-Month Efficacy and Safety Study of Testosterone Solution 2% for Sex Drive and Energy in Hypogonadal Men.

PURPOSE: We evaluated the continued safety and efficacy of testosterone solution 2% (T-sol) in a 6-month open label extension study following a 3-month, double-blind, placebo controlled study in which T-sol was safe and efficacious for sex drive in men with androgen deficiency. MATERIALS AND METHODS: A total of 558 hypogonadal participants with a mean (SD) age of 55 (11) years entered the open label treatment study. Of these patients 275 had previously received placebo (formerly placebo group) and 283 had received active treatment with T-sol (continuing active group) during the double-blind phase. Outcome measures were the proportion of men with total testosterone levels within the normal range; assessment of treatment induced change in sex drive measured using the Sexual Arousal, Interest, and Drive scale; and assessment of treatment induced change in energy measured using the Hypogonadism Energy Diary. RESULTS: At the completion of the open label phase 60% and 66% of the participants had total testosterone levels within the normal range in the formerly placebo and continuing active groups, respectively. Participants assigned to both groups showed baseline to end point improvement in Sexual Arousal, Interest, and Drive score (both p <0.001) and Hypogonadism Energy Diary score (both p <0.001) during the open label phase. No new safety concerns were reported. CONCLUSIONS: Once daily T-sol administered for 6 months in an open label study did not indicate new safety concerns, and the outcomes of low sex drive and low energy showed further improvement after the double-blind phase.

Effect of Testosterone Solution 2% on Testosterone Concentration, Sex Drive and Energy in Hypogonadal Men: Results of a Placebo Controlled Study.

PURPOSE: We determined the effect of testosterone solution 2% on total testosterone level and the 2 symptoms of hypogonadism, sex drive and energy level. MATERIALS AND METHODS: This was a randomized, multicenter, double-blind, placebo controlled, 16-week study to compare the effect of testosterone and placebo on the proportion of men with a testosterone level within the normal range (300 to 1,050 ng/dl) upon treatment completion. We also assessed the impact of testosterone on sex drive and energy level measured using SAID (Sexual Arousal, Interest and Drive scale) and HED (Hypogonadism Energy Diary), respectively. A total of 715 males 18 years old or older with total testosterone less than 300 ng/dl and at least 1 symptom of testosterone deficiency (decreased energy and/or decreased sexual drive) were randomized to 60 mg topical testosterone solution 2% or placebo once daily. RESULTS: Of study completers 73% in the testosterone vs 15% in the placebo group had a testosterone level within the normal range at study end point (p <0.001). Participants assigned to testosterone showed greater baseline to end point improvement in SAID scores (low sex drive subset p <0.001 vs placebo) and HED scores (low energy subset p = 0.02 vs placebo, not significant at prespecified p <0.01). No major adverse cardiovascular or venous thrombotic events were reported in the testosterone group. The incidence of increased hematocrit was higher with testosterone vs placebo (p = 0.04). CONCLUSIONS: Once daily testosterone solution 2% for 12 weeks was efficacious in restoring normal testosterone levels and improving sexual drive in hypogonadal men. Improvement was also seen in energy levels on HED though not at the prespecified p <0.01. No new safety signals were identified.

Prasugrel in children with sickle cell disease: pharmacokinetic and pharmacodynamic data from an open-label, adaptive-design, dose-ranging study.

INTRODUCTION: This phase 2 study was designed to characterize the relationship among prasugrel dose, prasugrel's active metabolite (Pras-AM), and platelet inhibition while evaluating safety in children with sickle cell disease. It was open-label, multicenter, adaptive design, dose ranging, and conducted in 2 parts. Part A: Patients received escalating single doses leading to corresponding increases in Pras-AM exposure and VerifyNow®P2Y12 (VN) platelet inhibition and decreases in VNP2Y12 reaction units and vasodilator-stimulated phosphoprotein platelet reactivity index. Part B: Patients were assigned daily doses (0.06, 0.08, and 0.12 mg/kg) based on VN pharmacodynamic measurements at the start of 2 dosing periods, each 14±4 days. Platelet inhibition was significantly higher at 0.12 mg/kg (56.3%±7.4%; least squares mean±SE) compared with 0.06 mg/kg (33.8%±7.4%) or 0.08 mg/kg (37.9%±5.6%). Patients receiving 0.12 mg/kg achieved ≥30% platelet inhibition; only 1 patient receiving 0.06 mg/kg exceeded 60% platelet inhibition. High interpatient variability in response to prasugrel and the small range of exposures precluded rigorous characterization of the relationship among dose, Pras-AM, and platelet inhibition. SAFETY: No hemorrhagic events occurred in Part A; 3 occurred in Part B, all mild and self-limited. CONCLUSIONS: Most children with sickle cell disease may achieve clinically relevant platelet inhibition with titration of daily-dose prasugrel.

Rehospitalization following percutaneous coronary intervention for commercially insured patients with acute coronary syndrome: a retrospective analysis.

BACKGROUND: While prior research has provided important information about readmission rates following percutaneous coronary intervention, reports regarding charges and length of stay for readmission beyond 30 days post-discharge for patients in a large cohort are limited. The objective of this study was to characterize the rehospitalization of patients with acute coronary syndrome receiving percutaneous coronary intervention in a U.S. health benefit plan. METHODS: This study retrospectively analyzed administrative claims data from a large US managed care plan at index hospitalization, 30-days, and 31-days to 15-months rehospitalization. A valid Diagnosis Related Group code (version 24) associated with a PCI claim (codes 00.66, 36.0X, 929.73, 929.75, 929.78-929.82, 929.84, 929.95/6, and G0290/1) was required to be included in the study. Patients were also required to have an ACS diagnosis on the day of admission or within 30 days prior to the index PCI. ACS diagnoses were classified by the International Statistical Classification of Disease 9 (ICD-9-CM) codes 410.xx or 411.11. Patients with a history of transient ischemic attack or stroke were excluded from the study because of the focus only on ACS-PCI patients. A clopidogrel prescription claim was required within 60 days after hospitalization. RESULTS: Of the 6,687 ACS-PCI patients included in the study, 5,174 (77.4%) were male, 5,587 (83.6%) were <65 years old, 4,821 (72.1%) had hypertension, 5,176 (77.4%) had hyperlipidemia, and 1,777 (26.6%) had diabetes. At index hospitalization drug-eluting stents were the most frequently used: 5,534 (82.8%). Of the 4,384 patients who completed the 15-month follow-up, a total of 1,367 (31.2%) patients were rehospitalized for cardiovascular (CV)-related events, of which 811 (59.3%) were revascularization procedures: 13 (1.0%) for coronary artery bypass graft and 798 (58.4%) for PCI. In general, rehospitalizations associated with revascularization procedures cost more than other CV-related rehospitalizations. Patients rehospitalized for revascularization procedures had the shortest median time from post-index PCI to rehospitalization when compared to the patients who were rehospitalized for other CV-related events. CONCLUSIONS: For ACS patients who underwent PCI, revascularization procedures represented a large portion of rehospitalizations. Revascularization procedures appear to be the most frequent, most costly, and earliest cause for rehospitalization after ACS-PCI.

Recovery of platelet function after discontinuation of prasugrel or clopidogrel maintenance dosing in aspirin-treated patients with stable coronary disease: the recovery trial.

OBJECTIVES: The goal of this study was to assess the offset of the antiplatelet effects of prasugrel and clopidogrel. BACKGROUND: Guidelines recommend discontinuing clopidogrel at least 5 days and prasugrel at least 7 days before surgery. The pharmacodynamic basis for these recommendations is limited. METHODS: Aspirin-treated patients with coronary artery disease were randomly assigned to either prasugrel 10 mg or clopidogrel 75 mg daily for 7 days. Platelet reactivity was measured before study drug administration and for up to 12 days during washout. The primary endpoint was the cumulative proportion of patients returning to baseline reactivity after study drug discontinuation. RESULTS: A total of 56 patients were randomized; 54 were eligible for analysis. Platelet reactivity was lower 24 h after the last dose of prasugrel compared with clopidogrel. After prasugrel, ≥75% of patients returned to baseline reactivity by washout day 7 compared with day 5 after clopidogrel. Recovery time was dependent on the level of platelet reactivity before study drug exposure and the initial degree of platelet inhibition after study drug discontinuation but not on treatment assignment. CONCLUSIONS: Recovery time after thienopyridine discontinuation depends on the magnitude of on-treatment platelet inhibition, resulting, on average, in a more delayed recovery with prasugrel compared with clopidogrel. The offset of prasugrel was consistent with current guidelines regarding the recommended waiting period for surgery after discontinuation. (Prasugrel/Clopidogrel Maintenance Dose Washout Study; NCT01014624).

Randomized trial evaluating serial protein C levels in severe sepsis patients treated with variable doses of drotrecogin alfa (activated).

INTRODUCTION: Serial alterations in protein C levels appear to correlate with disease severity in patients with severe sepsis, and it may be possible to tailor severe sepsis therapy with the use of this biomarker. The purpose of this study was to evaluate the dose and duration of drotrecogin alfa (activated) treatment using serial measurements of protein C compared to standard therapy in patients with severe sepsis. METHODS: This was a phase 2 multicenter, randomized, double-blind, controlled study. Adult patients with two or more sepsis-induced organ dysfunctions were enrolled. Protein C deficient patients were randomized to standard therapy (24 µg/kg/hr infusion for 96 hours) or alternative therapy (higher dose and/or variable duration; 24/30/36 µg/kg/hr for 48 to 168 hours). The primary outcome was a change in protein C level in the alternative therapy group, between study Day 1 and Day 7, compared to standard therapy. RESULTS: Of 557 patients enrolled, 433 patients received randomized therapy; 206 alternative, and 227 standard. Baseline characteristics of the groups were largely similar. The difference in absolute change in protein C from Day 1 to Day 7 between the two therapy groups was 7% (P = 0.011). Higher doses and longer infusions were associated with a more pronounced increase in protein C level, with no serious bleeding events. The same doses and longer infusions were associated with a larger increase in protein C level; higher rates of serious bleeding when groups received the same treatment; but no clear increased risk of bleeding during the longer infusion. This group also experienced a higher mortality rate; however, there was no clear link to infusion duration. CONCLUSIONS: The study met its primary objective of increased protein C levels in patients receiving alternative therapy demonstrating that variable doses and/or duration of drotrecogin alfa (activated) can improve protein C levels, and also provides valuable information for incorporation into potential future studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00386425.

Troponin-I as a prognosticator of mortality in severe sepsis patients.

PURPOSE: The purpose of this retrospective study was to evaluate cardiac troponin-I (cTnI) as a 28-day mortality prognosticator and predictor for a drotrecogin alfa (activated) (DrotAA) survival benefit in recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis patients. METHODS: Cardiac troponin-I was measured using the Access AccuTnI Troponin I assay (Beckman Coulter, Fullerton, CA). There were 598 patients (305 DrotAA, 293 placebo) with baseline cTnI data (cTnI negative [<0.06 ng/mL], n = 147; cTnI positive [>or=0.06 ng/mL], n = 451). RESULTS: Cardiac troponin-I-positive patients were older (mean age, 61 vs 56 years; P = .002), were sicker (mean Acute Physiology and Chronic Health Evaluation II, 26.1 vs 22.3; P < .001), had lower baseline protein C levels (mean level, 49% vs 56%; P = .017), and had higher 28-day mortality (32% vs 14%, P < .0001) than cTnI-negative patients. Elevated cTnI was an independent prognosticator of mortality (odds ratio, 2.020; 95% confidence interval, 1.153-3.541) after adjusting for other significant variables. Breslow-Day interaction test between cTnI levels and treatment was not significant (P = .65). CONCLUSION: This is the largest severe sepsis study reporting an association between elevated cTnI and higher mortality. Cardiac troponin-I elevation was not predictive of a survival benefit with DrotAA treatment.

Clinical diagnosis of lacunar stroke in the first 6 hours after symptom onset: analysis of data from the glycine antagonist in neuroprotection (GAIN) Americas trial.

BACKGROUND AND PURPOSE: Although the pathophysiological heterogeneity of stroke may be highly relevant to the development of acute-phase therapies, discriminating between ischemic stroke subtypes soon after onset remains a challenge. We conducted a study of the accuracy of a clinical diagnosis of lacunar stroke in the first 6 hours after symptom onset. METHODS: We analyzed data from 1367 patients in the Glycine Antagonist In Neuroprotection (GAIN) Americas trial. The Trial of ORG10172 in Acute Stroke Treatment (TOAST) category "small vessel (lacunar)" disease at day 7 or at hospital discharge was used as the reference standard to determine the accuracy of a diagnosis of a lacunar stroke made within 6 hours of symptom onset using the Oxfordshire Community Stroke Project (OCSP) classification "LACS." Outcome was analyzed by comparing the proportions of patients classified as "LACS" at baseline or "small vessel (lacunar)" at 7 days who were dead or dependent at 3 months. RESULTS: The positive predictive value of an OCSP diagnosis of a lacunar stroke was 76% (95% CI: 69% to 81%; sensitivity 64% [95% CI: 58% to 70%]; specificity 96% [95% CI: 95% to 97%]; negative predictive value 93% [95% CI: 92% to 94%]; accuracy 91% [95% CI: 89% to 92%]). The 3-month outcomes of patients classified as either OCSP "LACS" within 6 hours of onset or TOAST "small vessel (lacunar)" at 7 days were not significantly different. CONCLUSIONS: An OCSP LACS diagnosis made within 6 hours of stroke onset is reasonably predictive of a final diagnosis of "small vessel (lacunar)" disease made using TOAST criteria and has a similar relationship to outcome at 3 months.

Obesity does not alter the pharmacokinetics of drotrecogin alfa (activated) in severe sepsis.

BACKGROUND: Drotrecogin alfa (activated) [DrotAA] is approved for the reduction of mortality in adults with severe sepsis (sepsis with acute organ dysfunction) and high risk of death. Patients whose actual body weight was >135 kg were excluded from the Phase III PROWESS trial. OBJECTIVE: To compare exposure to DrotAA in patients with severe sepsis weighing >135 kg with those weighing < or =135 kg in an open-label, Phase IV trial, and quantify the elimination half-life (t1/2) of DrotAA in these patients. METHODS: PROWESS inclusion/exclusion criteria were used, except that patients >135 kg were enrolled. Blood samples were collected for steady-state plasma concentration (Css) analysis of activated protein C once each day and for t1/2 analysis after infusion. Weight-normalized clearance (Clp) and t1/2 estimates for DrotAA were calculated and compared between weight groups. RESULTS: Patient weight range was 59-227 kg. There were 32 patients < or =135 kg and 20 patients >135 kg enrolled. Median Clp was 0.45 L/h/kg (interquartile range [IQR] 0.37-0.54) for patients < or =135 kg and 0.42 L/h/kg (IQR 0.33-0.54) for patients >135 kg (p = 0.692). Median estimates of Css were 51.9 ng/mL (IQR 43.4-62.0) and 56.5 ng/mL (IQR 44.9-71.1; p = 0.570). In patients < or =135 kg, DrotAA had a median t1/2 of 16.7 minutes (IQR 13.9-20.0) compared with 16.0 minutes (IQR 12.9-19.8) in patients >135 kg (p = 0.767), for a composite median t1/2 of 16.3 minutes (IQR 14.2-18.8). CONCLUSIONS: There is no statistically significant difference in Css concentrations or t1/2 of DrotAA between patients weighing < or =135 kg and >135 kg. DrotAA should be dosed by actual body weight.

The clinical evaluation committee in a large multicenter phase 3 trial of drotrecogin alfa (activated) in patients with severe sepsis (PROWESS): role, methodology, and results.

OBJECTIVE: In the multinational PROWESS trial, drotrecogin alfa (activated) significantly reduced mortality rate in patients with severe sepsis compared with placebo. The use of large multiple-center trials can potentially complicate interpretation of results in severe sepsis populations because of variability in medical attitudes and practices and the frequency of confounding events such as protocol violations. The objective of this study was to perform a blinded, critical, integrated review of data from the 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial using a Clinical Evaluation Committee. DESIGN: Blinded, critical, integrated review of data. SETTING: Participating sites. PATIENTS: The 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial. INTERVENTIONS: We performed analyses of the optimal cohort, defined as patients who had full compliance with the protocol, had evidence of an infection, and received adequate anti-infective therapy. We also performed other analyses, including significant underlying disorders, life support measures, and causes of death. MEASUREMENTS AND MAIN RESULTS: The optimal cohort of 81.4% of the intention-to-treat population [drotrecogin alfa (activated), n = 695; placebo, n = 680] had similar baseline severity of illness between the two groups, a similar pharmacodynamic effect, and a relative risk of death estimate consistent with that observed in the overall PROWESS trial (0.83, 95% confidence interval 0.69-0.99 vs. 0.806, 95% confidence interval 0.69-0.94). A beneficial effect of drotrecogin alfa (activated) similarly was observed in patients with significant underlying disorders (0.73, 95% confidence interval 0.57-0.93) who were more severely ill and had a higher percentage of patients forgoing life-sustaining therapy. In contrast with the original investigator determinations, a benefit associated with drotrecogin alfa (activated) treatment in urinary tract infection adjudicated by the Clinical Evaluation Committee was observed. CONCLUSIONS: The survival benefit associated with drotrecogin alfa (activated) use was consistent with the results of the overall trial regardless of whether patients met criteria of the optimal cohort or had a significant underlying disorder.

Management of patients with severe sepsis, treated by drotrecogin alfa (activated).

A number of management issues confront the clinician treating a critically ill patient with drotrecogin alfa (activated) (Xigris; Eli Lilly and Company, Indianapolis, IN), a compound documented to significantly reduce the risk of 28-day all-cause mortality in patients with severe sepsis. The management issues that will be discussed include differentiating drug effect from the hemostatic changes of sepsis, prevention and management of bleeding during drotrecogin alfa (activated) infusion, treatment considerations in the patient with thrombocytopenia or disseminated intravascular coagulation, thromboprophylaxis in drug-treated patients, and the use of drotrecogin alfa (activated) in patients requiring renal replacement therapy. Proper adherence to principles described in this article can facilitate patient management and reduce the risk of bleeding.