David L. DeMets

Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework*

genome are dramatically reshaping the research and development pathways for drugs, vaccines, and diagnostics. The growth in the number of molecular entities entering the drug development pipeline has accelerated as a consequence of powerful discovery and screening technologies such as combinatorial chemistry, mass spectrometry, high throughput screening, celland tissue-based DNA microarrays, and proteomic approaches.1 As a consequence, there is an escalating number of therapeutic candidates, which has caused the need for new technologies and strategies to streamline the process to make safe and effective therapies available to patients. One approach to the achievement of more expeditious and informative therapeutic research is the use of precise clinical measurement tools to determine disease progression and the effects of interventions (drugs, surgery, and vaccines). For example, gene-based approaches such as single nucleotide polymorphism maps are now being developed to distinguish the molecular and cellular basis for variations in clinical response to therapy.2 Another approach is the use of a wide array of analytical tools to assess biological parameters, which are referred to as biomarkers. Biomarker measurements can help explain empirical results of clinical trials by relating the effects of interventions on molecular and cellular pathways to clinical responses. In doing so, biomarkers provide an avenue for researchers to gain a mechanistic understanding of the differences in clinical response that may be influenced by uncontrolled variables (for example, drug metabolism). There are a variety of ways that biomarker measurements can aid in the development and evaluation of COMMENTARY

Effect of Oral Milrinone on Mortality in Severe Chronic Heart Failure

BACKGROUND Milrinone, a phosphodiesterase inhibitor, enhances cardiac contractility by increasing intracellular levels of cyclic AMP, but the long-term effect of this type of positive inotropic agent on the survival of patients with chronic heart failure has not been determined. METHODS We randomly assigned 1,088 patients with severe chronic heart failure (New York Heart Association class III or IV) and advanced left ventricular dysfunction to double-blind treatment with (40 mg of oral milrinone daily (561 patients) or placebo (527 patients). In addition, all patients received conventional therapy with digoxin, diuretics, and a converting-enzyme inhibitor throughout the trial. The median period of follow-up was 6.1 months (range, 1 day to 20 months). RESULTS As compared with placebo, milrinone therapy was associated with a 28 percent increase in mortality from all causes (95 percent confidence interval, 1 to 61 percent; P = 0.038) and a 34 percent increase in cardiovascular mortality (95 percent confidence interval, 6 to 69 percent; P = 0.016). The adverse effect of milrinone was greatest in patients with the most severe symptoms (New York Heart Association class IV), who had a 53 percent increase in mortality (95 percent confidence interval, 13 to 107 percent; P = 0.006). Milrinone did not have a beneficial effect on the survival of any subgroup. Patients treated with milrinone had more hospitalizations (44 vs. 39 percent, P = 0.041), were withdrawn from double-blind therapy more frequently (12.7 vs. 8.7 percent, P = 0.041), and had serious adverse cardiovascular reactions, including hypotension (P = 0.006) and syncope (P = 0.002), more often than the patients given placebo. CONCLUSIONS Our findings indicate that despite its beneficial hemodynamic actions, long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe chronic heart failure. The mechanism by which the drug exerts its deleterious effects is unknown.

2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

Jeffrey L. Anderson, MD, FACC, FAHA, Chair , Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect , Nancy M. Albert, PhD, CCNS, CCRN, FAHA, Biykem Bozkurt, MD, PhD, FACC, FAHA, Ralph G. Brindis, MD, MPH, MACC, Mark A. Creager, MD, FACC, FAHA[§§][1], Lesley H. Curtis, PhD, FAHA, David DeMets, PhD,

The Wisconsin Epidemiologic Study of Diabetic Retinopathy: VI. Retinal Photocoagulation

The prevalence of focal and panretinal photocoagulation and its relationship to demographic and other characteristics were examined in a population-based study in southern Wisconsin. For participants whose age at diagnosis was less than 30 years and who were taking insulin (996 persons) the prevalence rate of panretinal photocoagulation (13.9%) was higher than that of focal photocoagulation (3.6%). For those whose age at diagnosis was 30 years or older (1370 persons), the prevalence rate for panretinal photocoagulation (3.6%) was slightly higher than that of focal photocoagulation (3.0%). Seventy-two percent of eyes of younger onset and 45% of eyes of older onset persons that had received panretinal photocoagulation treatment were found to have incomplete regression of retinal new vessels, and in approximately half of these eyes severe proliferative retinopathy (Diabetic Retinopathy Study High Risk Characteristics [DRS-HRC]) was present. Among eyes with DRS-HRC, 55% were found to be untreated.

Surrogate end points in clinical trials : Are we being misled ?

Clinical trials are the standard scientific method for evaluating a new biological agent, drug, device, or procedure for the prevention or treatment of disease in humans. The phase 3 trial is designed to evaluate a new agents clinical benefit and possible side effects; as such, it is considered to be the definitive test of the agents usefulness [1-3]. For phase 3 trials, the primary end point should be a clinical event relevant to the patient, that is, the event of which the patient is aware and wants to avoid. Examples are death, loss of vision, symptomatic events of the acquired immunodeficiency syndrome (AIDS), the need for ventilatory support, and other events causing a reduction in quality of life. Trials with these clinical outcomes often have a long duration and are expensive. As a consequence, there has recently been great interest in the development of alternative outcomes, or surrogate end points, to reduce the cost and shorten the duration of phase 3 trials [4-17]. As defined by Temple [13], a surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives. Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint. Examples of surrogate end points are increased CD4 cell counts or decreased viral load measures for trials of therapy for human immunodeficiency virus (HIV) infection or AIDS, suppression of ventricular arrhythmias or reduction in cholesterol level or blood pressure in cardiology trials, and tumor regression in trials of cancer therapy. Surrogate end points are rarely, if ever, adequate substitutes for the definitive clinical outcome in phase 3 trials. We review the basic requirements that the surrogate must meet to be used as the replacement outcome. Requirements for a Surrogate End Point A correlate does not a surrogate make. It is a common misconception that if an outcome is a correlate (that is, correlated with the true clinical outcome) it can be used as a valid surrogate end point (that is, a replacement for the true clinical outcome). However, proper justification for such replacement requires that the effect of the intervention on the surrogate end point predicts the effect on the clinical outcomea much stronger condition than correlation. Prentice [11] developed criteria that are sufficient to validate surrogate end points in phase 3 trials. These criteria essentially require that the surrogate must be a correlate of the true clinical outcome and fully capture the net effect of treatment on the clinical outcome. Although the first criterion is usually easy to verify, the second is not. For example, several recent trials on HIV and AIDS [14-24] showed that the second criterion is not satisfied when CD4 cell count is used as a surrogate end point for development of symptomatic AIDS events or death. Several factors, illustrated in Figure 1, may explain the failure of surrogate end points. Although it may be a correlate of disease progression (Figure 1A), a surrogate end point might not involve the same pathophysiologic process that results in the clinical outcome. Even when it does, some disease pathways are probably causally related to the clinical outcome and not related to the surrogate end point. Of the disease pathways affecting the true clinical outcome, the intervention may only affect the pathway mediated through the surrogate end point (Figure 1B) or the pathway or pathways independent of the surrogate end point (Figure 1C). Most important, the intervention might also affect the true clinical outcome by unintended mechanisms of action that are independent of the disease process (Figure 1D). The effects of the intervention mediated through intended mechanisms could be substantially offset by unintended, unanticipated, or unrecognized mechanisms [25]. Figure 1. Reasons for failure of surrogate end points. Figure 2 illustrates the setting that provides the greatest potential for the validity of the surrogate end point. Specifically, the surrogate is in the only causal pathway of the disease process, and the interventions entire effect on the true clinical outcome is mediated through its effect on the surrogate. Even in this ideal setting, however, surrogate end points can yield misleading conclusions. The interventions effect on the true clinical end point could be underestimated if there is considerable noise in the measurement of effects on the surrogate end point. The effect on the true end point could be overestimated if the effect on the surrogate, although statistically significant, is not of sufficient size or duration to meaningfully alter the true clinical outcome. This overestimation could readily arise, for example, in the ongoing evaluation of protease inhibitors in HIV-infected patients, in which effects on the surrogate end point (viral RNA levels in the peripheral blood) are substantial but of only short duration. Figure 2. The setting that provides the greatest potential for the surrogate end point to be valid. A review of recent experiences with surrogates is sobering, revealing many cases for which biological markers were correlates of clinical outcomes but failed to predict the effect of treatment on the clinical outcome. In the next section, we examine the failure of surrogates in several clinical trial settings by disease area. We can only speculate about the reasons for these failures because, even in retrospect, our understanding of the causal pathways of the disease process and the mechanisms of action of the intervention is incomplete. Table 1 provides such speculation, according to the possible explanations provided in Figure 1. Table 1. Speculation on Reasons for Failures of Surrogate End Points* Surrogate End Points in Cardiology Arrhythmia Suppression Use of reduction in ventricular ectopic contractions as a surrogate for decreased cardiovascular-related mortality provides a classic example of the unreliability of surrogate end points. Ventricular arrhythmia is associated with an almost fourfold increase in the risk for death related to cardiac complications [26, 27], particularly sudden death. It was hypothesized that suppression of ventricular arrhythmias after myocardial infarction would reduce the rate of death. Three new drugs (encainide, flecainide, and moricizine) were found to suppress arrhythmias effectively and were approved by the Food and Drug Administration (FDA) for use in patients with life-threatening or severely symptomatic arrhythmias. Although follow-up trials had not been done to determine whether the reduction in arrhythmias would lead to a reduction in death rates, more than 200 000 persons per year eventually took these drugs in the United States. The Cardiac Arrhythmia Suppression Trial (CAST) [26-28] evaluated how the three drugs would affect survival of patients who had had myocardial infarction and had at least 10 premature ventricular beats per hour. The early results from CAST were startling. The encainide and flecainide arms of the trial were terminated early when 33 sudden deaths occurred in patients taking either drug compared with only 9 in the matching placebo group. A total of 56 patients in the encainide and flecainide group died, and 22 patients in the placebo group died. After the data were finalized, the sudden death comparison was 43 and 16 and the number of deaths was 63 in the encainide and flecainide group and 26 in the placebo group. Later results from CAST also established an increased risk for death in patients receiving moricizine [28]. Two other examples are relevant to the arrhythmia setting. Quinidine has been used to maintain sinus rhythm after patients with atrial fibrillation have been converted [29]. A meta-analysis of six trials indicated that quinidine maintained sinus rhythm at 1 year (50% of patients who received quinidine compared with 25% of those who did not) but increased the mortality rate from 0.8% to 2.9%. Preventing recurrence of atrial fibrillation is an important benefit, but it does not outweigh the increased mortality rate. Similar inconsistencies were found for lidocaine; a meta-analysis showed that a one-third reduction in the risk for ventricular tachycardia was accompanied by a one-third increase in death rate [30, 31]. Exercise Tolerance in Congestive Heart Failure Patients with congestive heart failure have decreased cardiac output, characteristic symptoms of dyspnea and orthopnea, decreased exercise capacity, and a high risk for death. The annual mortality rate for patients with severe congestive heart failure is 20% to 40%. The poor exercise performance is presumed to be a result of decreased cardiac output, but it could also result from increased pulmonary vascular pressure. In this disease, cardiac output and ejection fraction have been used as surrogate end points for examining the usefulness of new drugs, and exercise tolerance and symptomatic improvement have also been regularly assessed as intermediate end points. Although some treatments that affect these end points produce improved survival [32-35], others provide no benefit or actually decrease survival. Diuretics and digoxin help alleviate symptoms. No data on the survival effects of these treatments have yet been published, although results of the recently reported Digitalis Investigation Group trial [36] show no survival benefit (American College of Cardiology, March 1996. Unpublished data). One of the earlier drugs that was proposed as a treatment for congestive heart failure was milrinone. Completed studies indicated that milrinone improved cardiac output and increased exercise tolerance. This drug is an inotropic agent (as is digoxin) that stimulates the force of contraction of the heart. Because the FDA was concerned that such agents may have adverse long-term effects (as was the case for -agonis

2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.

Developed in Collaboration With the American Association for Thoracic Surgery and Society of Thoracic Surgeons Andrew E. Epstein, MD, FACC, FAHA, FHRS, Chair ; John P. DiMarco, MD, PhD, FACC, FHRS; Kenneth A. Ellenbogen. MD, FACC, FAHA, FHRS; N.A. Mark Estes III, MD, FACC, FAHA, FHRS; Roger A.

Effects of Tamoxifen on Bone Mineral Density in Postmenopausal Women with Breast Cancer

BACKGROUND AND METHODS Tamoxifen, a synthetic antiestrogen, increases disease-free and overall survival when used as adjuvant therapy for primary breast cancer. Because it is given for long periods, it is important to know whether tamoxifen affects the skeleton, particularly since it is used extensively in postmenopausal women who are at risk for osteoporosis. Using photon absorptiometry, we studied the effects of tamoxifen on the bone mineral density of the lumbar spine and radius and on biochemical measures of bone metabolism in 140 postmenopausal women with axillary-node-negative breast cancer, in a two-year randomized, double-blind, placebo-controlled trial. RESULTS In the women given tamoxifen, the mean bone mineral density of the lumbar spine increased by 0.61 percent per year, whereas in those given placebo it decreased by 1.00 percent per year (P less than 0.001). Radial bone mineral density decreased to the same extent in both groups. In a subgroup randomly selected from each group, serum osteocalcin and alkaline phosphatase concentrations decreased significantly in women given tamoxifen (P less than 0.001 for each variable), whereas serum parathyroid hormone and 1,25-dihydroxyvitamin D concentrations did not change significantly in either group. CONCLUSIONS In postmenopausal women, treatment with tamoxifen is associated with preservation of the bone mineral density of the lumbar spine. Whether this favorable effect on bone mineral density is accompanied by a decrease in the risk of fractures remains to be determined.

Effect of Amlodipine on Morbidity and Mortality in Severe Chronic Heart Failure

BACKGROUND Previous studies have shown that calcium-channel blockers increase morbidity and mortality in patients with chronic heart failure. We studied the effect of a new calcium-channel blocker, amlodipine, in patients with severe chronic heart failure. METHODS We randomly assigned 1153 patients with severe chronic heart failure and ejection fractions of less than 30 percent to double-blind treatment with either placebo (582 patients) or amlodipine (571 patients) for 6 to 33 months, while their usual therapy was continued. The randomization was stratified on the basis of whether patients had ischemic or nonischemic causes of heart failure. The primary end point of the study was death from any cause and hospitalization for major cardiovascular events. RESULTS Primary end points were reached in 42 percent of the placebo group and 39 percent of the amlodipine group, representing a 9 percent reduction in the combined risk of fatal and nonfatal events with amlodipine (95 percent confidence interval, 24 percent reduction to 10 percent increase; P=0.31). A total of 38 percent of the patients in the placebo group died, as compared with 33 percent of those in the amlodipine group, representing a 16 percent reduction in the risk of death with amlodipine (95 percent confidence interval, 31 percent reduction to 2 percent increase; P=0.07). Among patients with ischemic heart disease, there was no difference between the amlodipine and placebo groups in the occurrence of either end point. In contrast, among patients with nonischemic cardiomyopathy, amlodipine reduced the combined risk of fatal and nonfatal events by 31 percent (P=0.04) and decreased the risk of death by 46 percent (P<0.001). CONCLUSIONS Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. The possibility that amlodipine prolongs survival in patients with nonischemic dilated cardiomyopathy requires further study.

Effect of Carvedilol on the Morbidity of Patients With Severe Chronic Heart Failure Results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study

Background—&bgr;-Blocking agents improve functional status and reduce morbidity in mild-to-moderate heart failure, but it is not known whether they produce such benefits in severe heart failure. Methods and Results—We randomly assigned 2289 patients with symptoms of heart failure at rest or on minimal exertion and with an ejection fraction <25% (but not volume-overloaded) to double-blind treatment with either placebo (n=1133) or carvedilol (n=1156) for an average of 10.4 months. Carvedilol reduced the combined risk of death or hospitalization for a cardiovascular reason by 27% (P =0.00002) and the combined risk of death or hospitalization for heart failure by 31% (P =0.000004). Patients in the carvedilol group also spent 27% fewer days in the hospital for any reason (P =0.0005) and 40% fewer days in the hospital for heart failure (P <0.0001). These differences were as a result of both a decrease in the number of hospitalizations and a shorter duration of each admission. More patients felt improved and fewer patients felt worse in the carvedilol group than in the placebo group after 6 months of maintenance therapy (P =0.0009). Carvedilol-treated patients were also less likely than placebo-treated patients to experience a serious adverse event (P =0.002), especially worsening heart failure, sudden death, cardiogenic shock, or ventricular tachycardia. Conclusion—In euvolemic patients with symptoms at rest or on minimal exertion, the addition of carvedilol to conventional therapy ameliorates the severity of heart failure and reduces the risk of clinical deterioration, hospitalization, and other serious adverse clinical events.

A Dose-Dependent Increase in Mortality with Vesnarinone among Patients with Severe Heart Failure

Background Vesnarinone, an inotropic drug, was shown in a short-term placebo-controlled trial to improve survival markedly in patients with severe heart failure when given at a dose of 60 mg per day, but there was a trend toward an adverse effect on survival when the dose was 120 mg per day. In a longer-term study, we evaluated the effects of daily doses of 60 mg or 30 mg of vesnarinone, as compared with placebo, on mortality and morbidity. Methods We enrolled 3833 patients who had symptoms of New York Heart Association class III or IV heart failure and a left ventricular ejection fraction of 30 percent or less despite optimal treatment. The mean follow-up was 286 days. Results There were significantly fewer deaths in the placebo group (242 deaths, or 18.9 percent) than in the 60-mg vesnarinone group (292 deaths, or 22.9 percent) and longer survival (P=0.02). The increase in mortality with vesnarinone was attributed to an increase in sudden death, presumed to be due to arrhythmia. The quality of life had ...