Howard C. Dittrich

Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) A Phase 2 Trial of Intracoronary Gene Therapy of Sarcoplasmic Reticulum Ca2+-ATPase in Patients With Advanced Heart Failure

Background— Adeno-associated virus type 1/sarcoplasmic reticulum Ca2+-ATPase was assessed in a randomized, double-blind, placebo-controlled, phase 2 study in patients with advanced heart failure. Methods and Results— Thirty-nine patients received intracoronary adeno-associated virus type 1/sarcoplasmic reticulum Ca2+-ATPase or placebo. Seven efficacy parameters were assessed in 4 domains: symptoms (New York Heart Association class, Minnesota Living With Heart Failure Questionnaire), functional status (6-minute walk test, peak maximum oxygen consumption), biomarker (N-terminal prohormone brain natriuretic peptide), and left ventricular function/remodeling (left ventricular ejection fraction, left ventricular end-systolic volume), plus clinical outcomes. The primary end point success criteria were prospectively defined as achieving efficacy at 6 months in the group-level (concordant improvement in 7 efficacy parameters and no clinically significant worsening in any parameter), individual-level (total score for predefined clinically meaningful changes in 7 efficacy parameters), or outcome end points (cardiovascular hospitalizations and time to terminal events). Efficacy in 1 analysis had to be associated with at least a positive trend in the other 2 analyses. This combination of requirements resulted in a probability of success by chance alone of 2.7%. The high-dose group versus placebo met the prespecified criteria for success at the group-level, individual-level, and outcome analyses (cardiovascular hospitalizations) at 6 months (confirmed at 12 months) and demonstrated improvement or stabilization in New York Heart Association class, Minnesota Living With Heart Failure Questionnaire, 6-minute walk test, peak maximum oxygen consumption, N-terminal prohormone brain natriuretic peptide levels, and left ventricular end-systolic volume. Significant increases in time to clinical events and decreased frequency of cardiovascular events were observed at 12 months (hazard ratio=0.12; P=0.003), and mean duration of cardiovascular hospitalizations over 12 months was substantially decreased (0.4 versus 4.5 days; P=0.05) on high-dose treatment versus placebo. There were no untoward safety findings. Conclusions— The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) study demonstrated safety and suggested benefit of adeno-associated virus type 1/sarcoplasmic reticulum Ca2+-ATPase in advanced heart failure, supporting larger confirmatory trials. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00454818.Background— Adeno-associated virus type 1/sarcoplasmic reticulum Ca2+-ATPase was assessed in a randomized, double-blind, placebo-controlled, phase 2 study in patients with advanced heart failure. Methods and Results— Thirty-nine patients received intracoronary adeno-associated virus type 1/sarcoplasmic reticulum Ca2+-ATPase or placebo. Seven efficacy parameters were assessed in 4 domains: symptoms (New York Heart Association class, Minnesota Living With Heart Failure Questionnaire), functional status (6-minute walk test, peak maximum oxygen consumption), biomarker (N-terminal prohormone brain natriuretic peptide), and left ventricular function/remodeling (left ventricular ejection fraction, left ventricular end-systolic volume), plus clinical outcomes. The primary end point success criteria were prospectively defined as achieving efficacy at 6 months in the group-level (concordant improvement in 7 efficacy parameters and no clinically significant worsening in any parameter), individual-level (total score for predefined clinically meaningful changes in 7 efficacy parameters), or outcome end points (cardiovascular hospitalizations and time to terminal events). Efficacy in 1 analysis had to be associated with at least a positive trend in the other 2 analyses. This combination of requirements resulted in a probability of success by chance alone of 2.7%. The high-dose group versus placebo met the prespecified criteria for success at the group-level, individual-level, and outcome analyses (cardiovascular hospitalizations) at 6 months (confirmed at 12 months) and demonstrated improvement or stabilization in New York Heart Association class, Minnesota Living With Heart Failure Questionnaire, 6-minute walk test, peak maximum oxygen consumption, N-terminal prohormone brain natriuretic peptide levels, and left ventricular end-systolic volume. Significant increases in time to clinical events and decreased frequency of cardiovascular events were observed at 12 months (hazard ratio=0.12; P =0.003), and mean duration of cardiovascular hospitalizations over 12 months was substantially decreased (0.4 versus 4.5 days; P =0.05) on high-dose treatment versus placebo. There were no untoward safety findings. Conclusions— The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) study demonstrated safety and suggested benefit of adeno-associated virus type 1/sarcoplasmic reticulum Ca2+-ATPase in advanced heart failure, supporting larger confirmatory trials. Clinical Trial Registration— . Unique identifier: [NCT00454818][1]. # Clinical Perspective {#article-title-37} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00454818&atom=%2Fcirculationaha%2F124%2F3%2F304.atom

Rolofylline, an Adenosine A1−Receptor Antagonist, in Acute Heart Failure

BACKGROUND Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1-receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure. METHODS We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patients clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes. RESULTS Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists. CONCLUSIONS Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.).

Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID Trial), a First-in-Human Phase 1/2 Clinical Trial

BACKGROUND SERCA2a deficiency is commonly seen in advanced heart failure (HF). This study is designed to investigate safety and biological effects of enzyme replacement using gene transfer in patients with advanced HF. METHODS AND RESULTS A total of 9 patients with advanced HF (New York Heart Association [NYHA] Class III/IV, ejection fraction [EF] < or = 30%, maximal oxygen uptake [VO2 max] <16 mL.kg.min, with maximal pharmacological and device therapy) received a single intracoronary infusion of AAV1/SERCA2a in the open-label portion of this ongoing study. Doses administered ranged from 1.4 x 10(11) to 3 x 10(12) DNase resistant particles per patient. We present 6- to 12-month follow-up data for these patients. AAV1/SERCA2a demonstrated an acceptable safety profile in this advanced HF population. Of the 9 patients treated, several demonstrated improvements from baseline to month 6 across a number of parameters important in HF, including symptomatic (NYHA and Minnesota Living with Heart Failure Questionnaire, 5 patients), functional (6-minute walk test and VO2 max, 4 patients), biomarker (NT-ProBNP, 2 patients), and LV function/remodeling (EF and end-systolic volume, 5 patients). Of note, 2 patients who failed to improve had preexisting anti-AAV1 neutralizing antibodies. CONCLUSIONS Quantitative evidence of biological activity across a number of parameters important for assessing HF status could be detected in several patients without preexisting neutralizing antibodies in this open-label study, although the number of patients in each cohort is too small to conduct statistical analyses. These findings support the initiation of the Phase 2 double-blind, placebo-controlled portion of this study.

Worsening renal function in patients hospitalised for acute heart failure: Clinical implications and prognostic significance

Renal function is a powerful prognostic variable in patients with heart failure (HF). Hospitalisations for acute HF (AHF) may be associated with further worsening of renal function (WRF).

Acute myocardial infarction in women: influence of gender on mortality and prognostic variables

The contention that mortality after acute myocardial infarction (AMI) is increased in women compared with men has been controversial, with findings in a recent multicenter study suggesting that gender plays an important prognostic role. To assess whether or not early and late mortality after AMI is greater in women, 2,089 patients (1,551 men, 538 women) were followed for 1 year after AMI. In the hospital, women had an increased mortality compared to men (17.5 vs 12.3%, p less than 0.003) and were on average 7 years older, whereas after hospital discharge and up to 1 year no difference in mortality was observed. Multivariate analyses of historical, clinical and laboratory features demonstrated that gender had no independent predictive value when variables that included age, congestive heart failure in the hospital, history of congestive failure, prior AMI and diabetes mellitus were considered. Moreover, when age stratification was performed, the significant difference of in-hospital mortality between genders was no longer present. Causes of death in the hospital and during 1 year after hospital discharge were similar between men and women, whether or not age stratification was performed. Several baseline clinical characteristics were different between men and women; a history of systemic hypertension and congestive heart failure occurred more frequently in women and previous AMI and smoking occurred more commonly in men. Also, the value of several other important prognostic indicators after AMI, such as the ejection fraction, was found to differ between men and women.(ABSTRACT TRUNCATED AT 250 WORDS)

Echocardiographic and clinical predictors for outcome of elective cardioversion of atrial fibrillation

Previous studies have suggested that success of elective direct-current cardioversion for atrial fibrillation (AF) can be predicted from clinical features and M-mode echocardiographic left atrial diameter. We evaluated clinical variables as well as M-mode and 2-dimensional echocardiographic measurements of atrial size in 85 patients undergoing electrical cardioversion for AF. Of 65 patients who were initially converted to sinus rhythm, 45 (69%) and 38 (58%) remained in sinus rhythm at 1 and 6 months, respectively. No historical feature predicted initial success, although patients with cardiomyopathy or pulmonary disease underlying their AF had significantly lower success rates compared with those having other etiologies. Furthermore, no M-mode or 2-dimensional echocardiographic measurements of atrial size predicted initial success of cardioversion. Maintenance of sinus rhythm at 1 month was related to short duration of AF before cardioversion (less than 3 months vs greater than 12 months, p less than 0.05). Left atrial area and long axis dimension by 2-dimensional echocardiography were significantly larger in patients remaining in sinus rhythm than in those who had reverted to AF at 1 month (28 +/- 7 vs 24 +/- 5 cm2 and 65 +/- 9 vs 59 +/- 8 mm, respectively, both p less than 0.05), but overlap was great. No significant difference in atrial dimensions was noted at 6-month follow-up. It appears that, although no clinical or echocardiographic variable predicts initial success for cardioversion of AF, duration of AF does predict maintenance of sinus rhythm 1 month after initial success.(ABSTRACT TRUNCATED AT 250 WORDS)

Differing circadian patterns of symptom onset in subgroups of patients with acute myocardial infarction.

Circadian variation of the onset of acute myocardial infarction has been noted in many studies and may carry important pathophysiologic implications. However, only a few previous studies have attempted subgroup analyses. In 4,796 patients with documented acute myocardial infarction, the time of symptom onset was recorded. As in other studies, the peak of onset occurred in the morning from 6:01 AM to 12:00 noon, and 28% of the population (1.16 times the average percentage for the other time periods) experienced symptom onset in that period (p less than 0.001). There was a second, lower peak (25%) in the evening between 6:01 PM and 12:00 midnight, which was also observed in some previous studies. We sought to determine whether or not the presence of subgroups with specific clinical characteristics would exhibit different patterns and thereby contribute to these peaks in the overall population. In patients with a history of congestive heart failure (n = 606) or with non-Q wave infarction (n = 832), a pronounced peak (29%) occurred only in the evening. Two nearly equal peaks were observed in patients older than 70 years of age (n = 1,422), smokers (n = 2,057), diabetics (n = 767), women (n = 1,213), and patients taking beta-blocking drugs (n = 847). Finally, in patients with a previous myocardial infarction (n = 1,104), no peaks were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Fluid overload in acute heart failure — Re-distribution and other mechanisms beyond fluid accumulation

Although fluid overload is one of the most prominent features of acute heart failure (AHF), its mechanism remains challenging, due to the lack of consistent data from prospective studies. Traditionally, fluid overload was thought to be mainly the result of either increased intake of fluid and salt or non‐adherence with diuretic therapy. However, recent data showed little weight change before or during an AHF event suggesting that in many cases fluid overload is caused by other mechanisms such as fluid redistribution and neurohormonal or inflammatory activation. Redistribution may be the result of a combined vascular and cardiac process reducing capacitance in the venous system (and hence increasing preload) and increasing arterial stiffness and resistance (and hence afterload). When these vascular processes occur acutely and are superimposed on reduced cardiac function; fluid is redistributed to the lungs instigating pulmonary congestion. In this paper we elaborate on this possible pathophysiological mechanism and review its potential causes and amplifiers.

The PROTECT pilot study: a randomized, placebo-controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment.

BACKGROUND Rolofylline, an adenosine A(1) receptor antagonist, facilitates diuresis and preserves renal function in patients with acute heart failure (AHF) with renal impairment. Although not powered around any specific hypothesis, this pilot study was designed to identify an efficacious dose while refining inclusion criteria and end points. METHODS A total of 301 patients hospitalized for AHF with an estimated creatinine clearance of 20 to 80 mL/min and elevated natriuretic peptide levels were enrolled within 24 hours of presentation to placebo or rolofylline 10, 20, or 30 mg administered as 4-hour infusions for 3 days in addition to intravenously administered loop diuretics. Post hoc analyses for end points chosen for subsequent Phase III studies were performed. RESULTS Compared with placebo, rolofylline produced trends toward greater proportions of patients with marked or moderately improved dyspnea and fewer patients with worsening heart failure or renal function. Serum creatinine increased in patients receiving placebo and remained stable or tended to decrease in those receiving rolofylline. On day 14 the absolute differences between placebo and rolofylline for change in creatinine increased with increasing rolofylline dose, reflecting the lesser increase in creatinine in rolofylline-treated patients (r = -0.12, P = .030). Treatment with 30 mg, the dose selected for the pivotal trials, was associated with a trend toward reduced 60-day mortality or readmission for cardiovascular or renal cause (hazard ratio, 0.55; 95% confidence interval, 0.28-1.04). CONCLUSION These results demonstrate that adenosine A(1) receptor blockade with rolofylline can prevent renal impairment in patients with AHF and may positively affect acute symptoms and 60-day outcome. A 2000-patient trial of this agent is now under way.

Myocardial infarction in young patients: an analysis by age subsets.

We examined, in age subsets, 2643 patients with acute myocardial infarction. Clinical features and 1 year morbidity and mortality were compared in 203 young patients (less than 45 years), 1671 patients 46 to 70 years old, and 769 elderly patients (greater than 70 years). Ninety-two percent of young patients were men, and a family history of premature coronary artery disease was more common in young patients (41% compared with 28% of middle-aged and 12% of elderly patients). More young patients were currently smoking cigarettes (82% compared with 56% of middle-aged and 24% of elderly patients), and only 8% of young patients had never smoked. Previous myocardial infarction and history of angina pectoris or congestive heart failure were less common (p less than .001) in the young patients than in middle-aged and elderly patients. In-hospital mortality was only 2.5% for young patients, compared with 9.0% in middle-aged and 21.4% in elderly patients (both p less than .001). Postdischarge 1 year mortality was also strikingly low in young patients, at 2.6% compared with 10.3% in middle-aged and 24.4% in elderly patients. The incidence of reinfarction during the 1 year of follow-up was similar in all subsets. The statistical significance of 65 variables as predictors of 1 year mortality and reinfarction was tested and the following found to be significant (p less than .05): hospital discharge on antiarrhythmic drugs, digoxin, or diuretics; history of previous myocardial infarction or congestive heart failure; chest x-ray findings of heart failure; low ejection fraction; and atrial fibrillation. Thus, young patients entering the hospital have an excellent 1 year prognosis, but those with prior infarction in whom there are selected abnormal findings at hospital discharge comprise a subgroup that may benefit from early aggressive management.