Use Of Aldosterone Antagonists Research Articles

Progressive ventricular dysfunction among nonresponders to cardiac resynchronization therapy: baseline predictors and associated clinical outcomes.

Cardiac resynchronization therapy (CRT) nonresponders have poor outcomes. The significance of progressive ventricular dysfunction among nonresponders remains unclear. We sought to define predictors of and clinical outcomes associated with progressive ventricular dysfunction despite CRT. We conducted an analysis of 328 patients undergoing CRT with defibrillator for standard indications. On the basis of 6-month echocardiograms, we classified patients as responders (those with a ≥5% increase in ejection fraction) and progressors (those with a ≥5% decrease in ejection fraction), and all others were defined as nonprogressors. Coprimary end points were 3-year (1) heart failure, left ventricular assist device (LVAD), transplantation, or death and (2) ventricular tachycardia (VT) or ventricular fibrillation (VF). Multivariable predictors of progressive ventricular dysfunction were aldosterone antagonist use (hazard ratio [HR] 0.23; P = .008), prior valve surgery (HR 3.3; P = .005), and QRS duration (HR 0.98; P = .02). More favorable changes in ventricular function were associated with lower incidences of heart failure, LVAD, transplantation, or death (70% vs 54% vs 33%; P < .0001) and VT or VF (66% vs 38% vs 28%; P = .001) for progressors, nonprogressors, and responders, respectively. After multivariable adjustment, progressors remained at increased risk of heart failure, LVAD, transplantation, or death (HR 2.14; P = .0029) and VT or VF (HR 2.03; P = .046) as compared with nonprogressors. Responders were at decreased risk of heart failure, LVAD, transplantation, or death (HR 0.44; P < .0001) and VT or VF (0.51; P = .015) as compared with nonprogressors. Patients with progressive deterioration in ventricular function despite CRT represent a high-risk group of nonresponders at increased risk of worsened clinical outcomes.

Rates of aldosterone antagonist use after myocardial infarction remain poor over time among guideline eligible patients

Rates of aldosterone antagonist use after myocardial infarction remain poor over time among guideline eligible patients

Abstract 158: Patient Characteristics Associated with Appropriate Use of Aldosterone Antagonist in a National Cohort of Veterans Hospitalized with Heart Failure

Background: Only 1 in 3 eligible Veterans receives an aldosterone antagonist (AA) after HF hospitalization. Our objective was to characterize the patient characteristics associated with appropriate AA prescription. Methods: From the VA External Peer Review Program, we identified a nationwide sample of Veterans with preexisting HF who were discharged from a VA hospital with a principal diagnosis of HF from 10/02 to 07/09. Patients were considered eligible for AA if they had LVEF ≤ 40%, serum creatinine ≤ 2.5 mg/dL for men/≤ 2.0 for women, serum potassium ≤ 5.0 meq/L, and were prescribed a beta-blocker or ACE-inhibitor or ARB at discharge. Patient demographics, vital signs, medications, labs, and coexisting illnesses were compared between patients who filled a prescription for an AA within 90 days of discharge versus those who did not. To examine patient-level predictors of aldosterone blocker fill among eligible patients, we used a generalized estimating equation adjusted for selected covariates to account for within hospital clustering. A backward selection procedure was used for covariate selection with a criterion of p&lt;0.10 for model entry and termination. Results: Of the total cohort (n=14,534), 64% (n=9,355) were eligible for an AA (mean age 70 years, mean serum creatinine 1.4 mg/dL, 70% white, 1% female). Beta-blocker and ACE/ARB use were each &gt; 90%. AA use was significantly associated (p&lt;.05) with younger age, black ethnicity, lower systolic BP, higher body mass index, hospitalization prior to 2008, lower comorbidity score, DM, liver disease, electrolyte disorders, depression, discharge prescription of loop or thiazide diuretics, beta blocker, warfarin, lower serum sodium, lower serum creatinine, and with having no history of metastatic cancer or drug abuse. Age and BP accounted for the greatest percentage of total variability in AA use. Conclusions: Patient characteristics associated with AA prescription were primarily clustered in the domains of age, ethnicity, HF severity-associated variables, potential contraindications, and comorbid conditions. It is unclear whether the association of increasing age with lower AA use is a disparity to be overcome or a safety concern. Certain patient characteristics, not previously reported, were found to be associated with AA use and may partially explain apparent gaps in appropriate use among Veterans.

Risk of Upper Gastrointestinal Bleeding From Different Drug Combinations

Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin increases the risk of upper gastrointestinal bleeding (UGIB). Guidelines suggest avoiding certain drug combinations, yet little is known about the magnitude of their interactions. We estimated the risk of UGIB during concomitant use of nonselective (ns)NSAIDs, cyclooxygenase -2 selective inhibitors (COX-2 inhibitors), and low-dose aspirin with other drugs. We performed a case series analysis of data from 114,835 patients with UGIB (930,888 person-years of follow-up) identified from 7 population-based health care databases (approximately 20 million subjects). Each patient served as his or her own control. Drug exposure was determined based on prescriptions of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin, alone and in combination with other drugs that affect the risk of UGIB. We measured relative risk (incidence rate ratio [IRR] during drug exposure vs nonexposure) and excess risk due to concomitant drug exposure (relative excess risk due to interaction [RERI]). Monotherapy with nsNSAIDs increased the risk of diagnosis of UGIB (IRR, 4.3) to a greater extent than monotherapy with COX-2 inhibitors (IRR, 2.9) or low-dose aspirin (IRR, 3.1). Combination therapy generally increased the risk of UGIB; concomitant nsNSAID and corticosteroid therapies increased the IRR to the greatest extent (12.8) and also produced the greatest excess risk (RERI, 5.5). Concomitant use of nsNSAIDs and aldosterone antagonists produced an IRR for UGIB of 11.0 (RERI, 4.5). Excess risk from concomitant use of nsNSAIDs with selective serotonin reuptake inhibitors (SSRIs) was 1.6, whereas that from use of COX-2 inhibitors with SSRIs was 1.9 and that for use of low-dose aspirin with SSRIs was 0.5. Excess risk of concomitant use of nsNSAIDs with anticoagulants was 2.4, of COX-2 inhibitors with anticoagulants was 0.1, and of low-dose aspirin with anticoagulants was 1.9. Based on a case series analysis, concomitant use of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin with SSRIs significantly increases the risk of UGIB. Concomitant use of nsNSAIDs or low-dose aspirin, but not COX-2 inhibitors, with corticosteroids, aldosterone antagonists, or anticoagulants produces significant excess risk of UGIB.

The impact of insurance and socioeconomic status on outcomes for patients with left ventricular assist devices

BackgroundThere has been a steady increase of patients living in the community with Left Ventricular Assist Devices (LVADs). There is a significant gap in our fund of knowledge with respect to the impact that insurance and socioeconomic status has on outcomes for LVAD patients. We thus hypothesize that low neighborhood socioeconomic status and receipt of Medicaid, respectively, lead to earlier readmissions, earlier death, as well as longer time to transplantation among LVAD patients. MethodsThis was a retrospective review of 101 patients using existing data in the medical information warehouse database at The Ohio State University Medical Center. Primary outcomes measured included time to first event (first readmission or death), death, and time to rehospitalization. Our secondary outcome of interest included time from LVAD implantation to cardiac transplantation. ResultsRecipients of Medicaid did not have an increased risk of adverse events compared with patients without Medicaid coverage. Low Median Household Income (MHI) was associated with an increased risk of readmission (log-rank P = 0.0069) and time to first event (log-rank P = 0.0088). Bridge to transplantation was the only independent predictor of time to death (Hazard Ratio 2.1, [95% confidence interval = 1.03–4.37]). Low MHI and a history of atherosclerosis were both significant predictors for readmission and time to first event. Aldosterone antagonist use decreased the risk of readmission or time to first event by 46%. ConclusionsLVAD recipients with a low MHI were more likely to be readmitted to the hospital after LVAD implantation. Whether these patients are adequately monitored on an outpatient basis remains unclear.

Tratamiento con diuréticos en la insuficiencia cardíaca aguda

Diuretics are widely recommended in patients with acute heart failure (AHF). Unfortunately, despite their widespread use, limited data are available from randomized clinical trials to guide clinicians on the appropriate management of diuretic therapy. Loop diuretics are considered the first-line diuretic therapy, especially intravenous furosemide, but the best mode of administration (high-dose versus low-dose and continuous infusion versus bolus) is unclear. When diuretic resistance develops, different therapeutic strategies can be adopted, including combined diuretic therapy with thiazide diuretics and/or aldosterone antagonists. Low or “non-diuretic” doses (25–50mg QD) of aldosterone antagonists have been demonstrated to confer a survival benefit in patients with heart failure and reduced ejection fraction and consequently should be prescribed in all such patients, unless contraindicated by potassium and/or renal function values. There is less evidence on the use of aldosterone antagonists at higher or “diuretic” doses (≥ 100mg QD) but these drugs could be useful in relieving congestive symptoms in combination with furosemide. Thiazide diuretics can also be helpful as they have synergic effects with loop diuretics by inhibiting sodium reabsorption in distal parts of the nephron. The effect of diuretic therapy in AHF should be monitored with careful observation of clinical signs and symptoms of congestion. Serum electrolytes and kidney function should also be monitored during the use of intravenous diuretics.

Hipertensión arterial resistente

The prevalence of resistant arterial hypertension (RH) is approximately 10-12%. Ambulatory Blood Pressure Monitoring is highly recommended in these patients to define true and white-coat RH since the latter group has a better prognosis. If well tolerated, a triple therapy plan including a diuretic, an ACE inhibitor or an angiotensin receptor blocker, and a calcium channel blocker is recommended. Regarding second-line drugs, most evidence has focused on the use of aldosterone antagonists. Data from short-term studies have suggested that percutaneous renal sympathetic denervation is a safe and effective therapeutic option in carefully selected patients with RH. However, long-term studies with large patient populations that evaluate the appearance of cardiovascular events are needed.

Lazy lips: hyperkalemia and acute tetraparesis-a case report from an urban emergency department.

A 58-year-old male patient was admitted to our emergency department at a large university hospital due to acute onset of general weakness. It was reported that the patient was bradycardic at 30/min and felt an increasing weakness of the limbs. At admission to the emergency department, the patient was not feeling any discomfort and denied dyspnoea or pain. The primary examination of the nervous system showed the cerebral nerves II–XII intact, muscle strength of the lower extremities was 4/5, and a minimal sensory loss of the left hemisphere was found. In addition, the patient complained about lazy lips. During ongoing examinations, the patient developed again symptomatic bradycardia, accompanied by complete tetraplegia. The following blood test showed severe hyperkalemia probably induced by use of aldosterone antagonists as the cause of the patient's neurologic symptoms. Hyperkalemia is a rare but treatable cause of acute paralysis that requires immediate treatment. Late diagnosis can delay appropriate treatment leading to cardiac arrhythmias and arrest.

Gap between clinical guidelines and practice: The case of aldosterone-antagonists in patients with myocardial infarction

Gap between clinical guidelines and practice: The case of aldosterone-antagonists in patients with myocardial infarction

Physician Underutilization of Effective Medications for Resistant Hypertension at Office Visits in the United States: NAMCS 2006–2010

The American Heart Association (AHA) published guidelines for treatment of resistant hypertension in 2008 recommending use of thiazide diuretics (particularly chlorthalidone), aldosterone antagonists, and fixed-dose combination medications, but it is unclear the extent to which these guidelines are being followed. To describe trends in physician use of recommended medications for resistant hypertension and assess variations in medication use based on geography, physician specialty and patient characteristics. Cross-sectional analysis using the National Ambulatory Medical Care Survey from 2006 to 2010. We analyzed visits of hypertension patients to family physicians, general internists, and cardiologists. Resistant hypertension was defined as concurrent use of ≥ 4 classes of blood pressure (BP) medications or elevated BP despite the use of ≥ 3 medications. Pregnant patients and visits with diagnosed heart failure or end-stage renal disease were excluded. Use of AHA-recommended medications for management of resistant hypertension. Of 19,500 patient visits with hypertension, 1,567 or 7.1 % CI (6.6-7.7 %) met criteria for resistant hypertension. Thiazide diuretic use was reported in 58.9 % of visits pre-guidelines vs. 54.8 % post-guidelines (p = 0.37). Use of aldosterone antagonists was low and also did not change significantly after guideline publication (3.1 % vs. 4.5 %, p = 0.27). Fixed-dose combinations use was 42.0 % before and 37 % after guideline publication (p = 0.29). Each 10-year increase in patient age was associated with lower thiazide use (OR 0.87, CI 0.77-0.97), as was presence of comorbid ischemic heart disease (OR 0.62, CI 0.41-0.94). Medication use did not vary by geography or physician specialty. Use of AHA-recommended medications for resistant hypertension remains low after publication of guidelines. Healthcare systems should encourage more frequent prescribing of these medications to improve care in this high-risk population.

Aldosterone Antagonists in Heart Failure

Chronic, systolic heart failure is an increasing and costly health problem, and treatments based on pathophysiology have evolved that include the use of aldosterone antagonists. Advances in the understanding of neurohormonal responses to heart failure have led to better pharmacologic treatments. The steroid hormone aldosterone has been associated with detrimental effects on the cardiovascular system, such as ventricular remodeling and endothelial dysfunction. This article will review the literature and guidelines that support the use of aldosterone antagonists in the treatment of chronic, systolic heart failure. Aldosterone antagonists are life-saving drugs that have been shown to decrease mortality in patients with New York Heart Association class III to IV heart failure and in patients with heart failure after an acute myocardial infarction. Additional studies are being conducted to determine if the role of aldosterone antagonists can be expanded to patients with less severe forms of heart failure. Aldosterone antagonists are an important pharmacologic therapy in the neurohormonal blockade necessary in the treatment of systolic heart failure. These drugs have been shown to decrease mortality and reduce hospital readmission rates. The major complication of aldosterone antagonists is hyperkalemia, which can be avoided with appropriate patient selection and diligent monitoring.

Niedokrwienie Serca i Nadciśnienie Tętnicze u Chorych na Przewlekłą Obturacyjną Chorobę płuc i Obturacyjny Bezdech Senny

Chronic obstructive pulmonary disease (COPD) affects almost 10% of the adult population of our country; obstructive sleep apnoea is increasingly being recognized and concerns, according to accepted criteria, 2-9% of females and 4-24% of men. The greatest mortality in chronic obstructive pulmonary disease is not caused by respiratory failure, but cardiovascular complications, including ischaemic heart disease. Obstructive sleep apnoea in half the cases is complicated by hypertension, often refractory to antihypertensive therapy. The paper discusses the pathogenesis of ischaemic heart disease in patients with COPD with particular attention to the inflammation that occurs in these two diseases. The pathogenesis of hypertension in the course of obstructive sleep apnoea is also presented with particular emphasis on hypoxia and sympathetic stimulation. Prevention of coronary heart disease should be a priority of the procedure in chronic obstructive pulmonary disease. The paper also discusses the treatment of ischaemic heart disease, paying attention to the modification of treatment in patients with chronic obstructive pulmonary disease, and discussing the influence of drugs used in COPD on the progression of ischaemic heart disease. Hypertension in the course of obstructive sleep apnoea is often resistant to therapy despite the use of continuous positive airway pressure devices, and often decrease after the use of aldosterone antagonists. Attention is drawn to the anti-inflammatory action of statins and trials of their use in the prevention of exacerbations of chronic obstructive pulmonary disease.

Clinical Implications

Clinical Implications

Most Important Outcomes Research Papers on Device Therapies for Cardiomyopathies

Disorders of the cardiac muscle or cardiomyopathies are a broad, yet collectively common, group of conditions. Despite the heterogeneous etiologies, mode of death from these conditions is remarkably similar - progressive decline in cardiac function leading to intractable heart failure (HF) and sustained ventricular arrhythmias resulting in sudden cardiac death (SCD). Nearly 50% of patients die within 5 years of a HF diagnosis.1 Indeed, in the United States, HF alone is thought to cause 55,000 deaths per year2 and further contribute to 1 in 9 deaths overall.1 However, while advanced HF and the risk of SCD were once thought to be untreatable, technological advances has seen the emergence of device therapies as viable treatment options. Specifically, implantable cardioverter-defibrillator (ICD) therapy for treatment of ventricular arrhythmias, cardiac resynchronization therapy (CRT) for restoring cardiac synchrony and mechanical efficiency, and ventricular assist device (VAD) therapy to temporarily or permanently replace the function of the failing heart, have all emerged as highly efficacious therapies. The expanding use of device therapies, however, poses many challenges. First, while the indications for these devices are well summarized in clinical guidelines,3,4 considerable hurdles remain in ensuring eligible patients receive these therapies.5 By the same token, establishing the safety and effectiveness of these therapies in populations that are found in clinical practice, yet commonly excluded from trials, such as the elderly6 and uncommon forms of cardiomyopathies,7 is a high priority. Second, rapid dissemination of technologies frequently results in disparities in care. Indeed, age, gender, and racial disparities, in both receipt of these devices and outcomes following implantation, have been well documented. Whether these disparities have persisted, and the potential causative mechanisms underlying these disparities, however, are uncertain.8,9 Third, these devices are not without significant untoward effects; understanding …

Use of aldosterone antagonists at discharge after myocardial infarction: Results from the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry–Get with the Guidelines (GWTG)

Aldosterone antagonists (AldA) improve survival after myocardial infarction (MI) in patients with left ventricular systolic dysfunction (ejection fraction [EF] <40%) concomitant with either clinical heart failure (HF) or diabetes mellitus (DM). Although current American College of Cardiology/American Heart Association guidelines provide a class I recommendation for AldA therapy in such patients, how US practice reflects these recommendations is unclear. Using data from the National Cardiovascular Data Registry ACTION Registry-GWTG, we describe contemporary discharge AldA prescription patterns among 202,213 patients discharged after acute MI from 526 US sites participating in ACTION Registry-GWTG between January 2007 and March 2011. Overall, 10.0% of patients were eligible for AldA without documented contraindication, with only 14.5% of eligible patients receiving AldA at discharge. Among the subset of AldA-eligible patients discharged on otherwise optimal medical therapy (68.9%), AldAs were prescribed to 16.1%. Aldosterone antagonist use was higher in patients with EF <40% and clinical HF with or without DM (17.7% and 16.6%, respectively), compared with patients with EF <40% and DM without clinical HF (7.8%, P < .001 for each). Fewer than 2% of participating centers used AldA in ≥50% of eligible patients. Despite clinical outcome evidence and class I guideline recommendations, AldAs are underused in the United States, with only 1 in 7 eligible patients prescribed AldA at discharge after MI. This contrasts with high use of other evidence-based post-MI medications and identifies a specific gap in translation of evidence into clinical practice.

Missed opportunities: low use of evidence-based treatment with eplerenone after myocardial infarction - a nationwide study

Purpose: The aldosterone antagonist eplerenone reduces mortality and readmissions after acute myocardial infarction (MI) in patients with LVEF≤40% and either symptomatic heart failure or diabetes mellitus, and is recommended by ESC guidelines. We investigated evidence-based use of eplerenone in a nationwide cohort of patients after first-time MI in Denmark. Methods: From national registers we included all patients with MI, aged ≥30 years and surviving ≥30 days. Indication for eplerenone was defined as claimed prescription of loop-diuretics in addition to either ACE-inhibitor or antidiabetic drugs, within 90 days after discharge. Use of eplerenone and other aldosterone antagonists was identified, and survival compared by Kaplan-Meier analysis. Results: We included 49,479 patients (63% men, mean age 68.1±13.6 years) with a median follow-up of 1003 (IQR 420-1716) days. Treatment with eplerenone was indicated in 9,115 (18.4%) patients, of which 93 (1.02%) received eplerenone, and 2,157 (23.7%) received spironolactone. Mortality rates for groups with and without indication for eplerenone at one-year were 1,096 (16.0%) and 3,115 (8.1%), and at end of follow-up 2,871 (41.8%) and 8,680 (22.5%), respectively (Figure). Applying the evidence-based mortality reducing effect of eplerenone to our results, a potential of 164 and 431 deaths within the first year, and during long-term follow-up, respectively, could have been saved by guideline-recommended use of eplerenone. ![Figure][1] Survival by eplerenone indication Conclusions: In a nationwide cohort of post-MI patients, a low use of eplerenone was observed in patients with indication for treatment. Our findings suggest an unexploited potential in the treatment of high-risk group of patients, and therefore focus on initiation of evidence-based treatment is warranted. [1]: pending:yes

New Heart Failure Guidelines Improve Prognosis, Quality of Life

New Heart Failure Guidelines Improve Prognosis, Quality of Life

Abstract 326: Low Rates Of Utilization Of Aldosterone Antagonists In Eligible Patients Post Myocardial Infarction: Insights From The Triumph And Premier Registries

Background: Current guidelines recommend initiation of an aldosterone antagonist post myocardial infarction (MI) for those with an ejection fraction (EF) &lt;40% with heart failure (HF) or diabetes mellitus (DM) prior to hospital discharge in the absence of contraindications. We assessed rates of guideline concordant and discordant use of aldosterone antagonists at discharge and 1 month post-MI. Method: Data was analyzed from combined PREMIER and TRIUMPH registries: a prospective, 31-center U.S. study of AMI outcomes from 2003 to 2008. We assessed rates of guideline concordant and discordant utilization of aldosterone antagonists among 6,329 therapy-naïve patients surviving their hospitalization with data available on EF, creatinine and potassium at discharge. Medication utilization at 1 month post discharge was assessed through interviews. Results: In the entire cohort, 678 patients were eligible for aldosterone antagonists; however, only 15.2% (n=103) received it. Among eligible patients (n=55) discharged on an aldosterone antagonist who completed 1month interviews, 27% (n=15) had discontinued it. Furthermore, among those who were eligible but were not discharged on an aldosterone antagonist (n=322), only 7.5% (n=24) were initiated on them post discharge at 1 month. Guideline discordant use of aldosterone antagonists was observed in only 2.0% (n= 113 of 5,651) patients: ~1% had EF ≥40%, others either did not have HF and DM or had potassium ≥5 mEq/L at discharge. Conclusion: We found that less than 1 in 6 eligible patients were prescribed aldosterone antagonists at discharge and of those prescribed them, 1 in 4 stopped within 1 month. These results extend our knowledge on under utilization of aldosterone antagonist therapy at discharge as well as on follow up. Future work is needed to assess reasons for this underutilization in eligible patients despite a proven benefit in randomized trials and a class I recommendation in guidelines.

Abstract 346: Use of Aldosterone Antagonists at Discharge in Eligible Heart Failure Patients With a Comprehensive Heart Failure Program: Trends in Compliance With Get With the Guidelines-Heart Failure

Background: Use of aldosterone antagonist (AA) therapy is a class I recommendation in moderate to severe heart failure (HF). Multiple studies have reported the underutilization of AA in eligible patients. We wished to analyze determining factors for this ongoing underutilization using the AHA’s Get With the Guidelines (GWTG) HF database from American Heart Association (AHA). We hypothesized that elevated creatinine is a major barrier to use of AA. Methods: A comprehensive HF program utilizing the GWTG measures was recently established at our institution. Outcome data utilizing the GWTG registry from January 2009 to June 2012 was analyzed. Given ACC/AHA guidelines that creatinine should be &lt; 2.5 mg/dL in men or &lt; 2.0 mg/dL in women, we chose to analyze genders separately. To analyze effect of degree of creatinine elevation on AA therapy at discharge, two subcategories of creatinine levels were analyzed. Creatinine levels above 2.0 mg/dL in women and 2.5 mg/dL in men were excluded, as AAs are contraindicated in these patients. Categorical variables were compared using the chi-square test. Results: Our total compliance rate with AA therapy at discharge during the study period was 26% (149 of 565) for females and 31% (199 of 640) for males. There was no significant decline in compliance when creatinine levels were &gt;1 mg/dL. Additionally, when comparing rates of compliance according to creatinine level across gender, there was no statistically significant difference in the use of AAs (see Table). Conclusion: Overall, AA therapy compliance at discharge at our center, as well as a majority of nationally recognized HF center participating in GWTG-HF registry remains suboptimal, irrespective of gender. This is despite known data that has clearly shown AAs significantly reduce mortality, cardiovascular death, HF hospitalizations and the composite endpoints. In contrast to prior studies, mild creatinine elevation does not seem to be a significant barrier to presciption of AAs. It is possible that other variables such as polypharmacy, hyperkalemia and effects of dual blockade of the renin-angiotensin-aldosterone system and the possibility of endocrine side effects associated with the non-selective AAs may be playing a role. More aggressive and consistent use of AA therapy for HF is warranted.

Drugs and Trials: Lessons From Plato

t l t e An article appears in the medical literature reporting a previously unrecognized side effect of a drug. It may be the unexpected appearance of a rare complication such as osteonecrosis of the jaw in patients who are treated with bisphosphonates. On other occasions, it is an increased frequency of a well-recognized adverse event such as hyperkalemia in conjunction with the use of aldosterone antagonists. Usually, the assessment of risk occurs in medical journals. The new information is incorporated into practice and clinicians adjust their prescription of the drug based on their interpretation of the needs of each patient. However, more often than we care to admit, reports of an adverse event are accompanied by evidence of misconduct either by physicians prescribing the drug or the pharmaceutical company that manufactures the drug. Suddenly, the affair is prominently featured on the front pages of The New York Times and plays out in the public arena. The US Food and Drug Administration (FDA) weighs in, “black box” warnings are published, drug use is severely restricted or banned, legal proceedings are started, and sanctions are imposed. Finally, the dust settles and physicians who are prescribing the drug appropriately in clinical practice or in research trials look up and find that they can no longer prescribe an agent that they judge to be useful for their patients. Rosiglitazone is a prominent example of a recent drug in which this sorry tale unfolded in the lay media and medical press. It followed shortly after the rofecoxib fiasco that came to light in 2004. I have been involved with clinical trials of rosiglitazone as the principal investigator of an ongoing randomized clinical trial in patients with resistant focal segmental glomerulosclerosis (FSGS) that was getting underway at about the same time as the publication of a meta-analysis of the safety outcomes of trials of rosiglitazone in adults with type 2 diabetes mellitus. The Novel Therapies for Resistant FSGS Trial (FONT) (DK70341; NCT00193648) is designed to test antifibrotic therapies that may attenuate the progressive decline in renal function in patients with FSGS