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A Placebo-Controlled Safety and Pharmacology Study of ALT-711 in Older Patients with Stiffened Cardiovasculature - A Placebo-Controlled Safety and Pharmacology Study of ALT-711 in Older Patients with Stiffened Cardiovasculature
Hypothesis:
To determine whether ALT-711 increases arterial distensibility in aged human subjects with vasculature hypertrophy
Study Design
Study Design:
Patients Enrolled: 93
Patient Populations:
93 patients with well-matched baseline characteristics, including systolic and diastolic blood pressures (BP); cardiac output was essentially normal and similar. Entry criteria were a resting systolic BP >140 mm Hg, resting pulse pressure was >60 mm Hg, and resting large artery compliance was <1.2 mL/mm Hg.
Primary Endpoints:
Pulse pressure, distensibility, tolerability, adverse reactions
Drug/Procedures Used:
ALT-711, a novel thiazolium derivative that breaks age cross-links, vs. placebo. After initial screening and randomization, patients followed at days 3, 7, 14, 28, 42, and 56 with early morning seated arm blood pressures plus Doppler echocardiography analysis at baseline, day 28 and day 56. Investigators developed a method to mathematically translate the wave form created by the radial pulse tracing into an estimated central aortic pressure wave form from which they could determine total arterial vasculature compliance using traditional models. Arterial distensibility was measured by dividing stroke volume by pulse pressure ratio; additional measures came from cardiac output and systemic resistance. Safety tolerance data were obtained through clinical laboratory tests and adverse experience reports.
Principal Findings:
- The ALT-711 group demonstrated a significant decline in pulse pressure vs. placebo (p<0.03), although this was not due to a greater decline in mean pressure; mean pressure change was minimal and similar in both groups. Thus the disparity in pulse pressure is not due to a drop in mean distending pressure.
- At day 28, ALT-711 significantly increased total artery compliance (p<0.005) and vascular distensibility (p<0.05); in the placebo group, both measurements were reduced. Similar results were seen at day 56.
- Neither cardiac output nor systemic vascular resistance changed from baseline to day 56. Thus, it appears that ALT-711 is not altering compliance by changing distal resistance smooth muscle tone, but rather targeting more proximal vessels.
- The placebo group showed the anticipated inverse relationship between mean arterial blood pressure and the corresponding changes in arterial distensibility or vascular compliance. The higher the change in mean pressure, the lower the reading of distensibility or compliance. In contrast, in the ALT-711 group, the relationship was substantially flattened. Indeed, even ALT-711 patients with increased blood pressure over the course of the trial showed increased compliance (p<0.005 for distensibility and compliance).
- The drug was generally well tolerated; there were reports of adverse experiences from 61.3% placebo patients and 54.8% ALT-711 patients. Most of these experiences included upper respiratory tract infections, diarrhea, headache, and non-specific pain; few were thought to be related to the drug treatment.
- In each arm, 6.5% of patients reported serious adverse events. Two of the ALT-711 patients had atrial fibrillation (in 1, this was a new event), 1 had non-cardiac chest pain that later proved to be from breast cancer, and 1 developed a sensation of numbness and discoordination and withdrew from the trial. In the placebo group, 1 experienced uncontrolled hypertension and another lung neoplasm.
- According to investigators, ALT-711 improved arterial distensibility or large artery compliance in aged individuals with stiffened vasculatures. This was associated with a reduction of the arterial pulse pressure. These changes could not be ascribed to altered mean arterial pressure or systemic resistance, but appear to reflect targeting of the agent to the larger vessels. ALT-711 is well tolerated and had few apparent side effects in this Phase IIA trial.
Interpretation:
It has been long recognized that the arterial pulse undergoes profound changes with aging. While the mean pressure itself increases only slightly, there is a substantial widening of the pulse excursions or pulse pressure, which is associated with elevation of systolic pressure and often a decline in arterial diastolic pressure. What has been more recently appreciated is that this increase in blood pressure pulsatility is itself a dominant risk factor for cardiovascular disease, particularly in the elderly. Recent epidemiologic trials have shown that even a 10 mm of mercury reduction in pulse pressure can lead to as much as a 20% decline in overall cardiovascular morbidity.
Increasing pulse pressure leads to arterial hypertrophy and structural remodeling, and contributes to atherogenesis, increases systolic load on the left ventricle resulting in ventricular hypertrophy, and is a dominant risk factor for coronary heart disease, myocardial infarction and congestive heart failure, particularly in individuals >60 years of age.
The mechanisms resulting in increased pulsatility are thought largely related to vascular stiffening. The mechanisms for stiffening involve degeneration of the elastic media, particularly of the large vessels; endothelial dysfunction within these arteries; increases in the mean distending pressure, since any artery becomes stiffer the higher its mean pressure; vascular remodeling; and dilatation, which pushes the artery out towards its collagen stress limits. Also, recently, there is evidence that cross links due to glucose protein interactions on structural proteins, such as collagen and elastin, lead to advanced glycosylation end (AGE) products and contribute to stiffening of the arteries.
In a non-enzymatic reaction, ALT-711 cleaves AGE cross-links, resulting in 2 separated proteins, releasing the agent itself. Because it is not consumed, the agent can feed back and enter this reaction again. In pre-clinical trials, ALT-711 improved large artery compliance in diabetic rats (Wolffenbuttel et al. PNAS 1998;95:4630), reduced myocardial stiffness in aged dogs (Asif et al. PNAS, 2000:97:2809), and most recently reduced both arterial pulse wave velocity and the augmentation index while enhancing ventricular stroke volume in older, non-human primates (Vaitkeviscius et al. PNAS 2001;98:1171).
Thus, ALT-711 may provide a novel therapeutic approach for reducing vascular stiffening and thereby lowering cardiovascular risks associated with increased blood pressure pulsatility. Further studies are planned to test the efficacy of ALT-711 in patients with systolic hypertension, and with an increased arterial pulse pressure with or without diabetes.
References:
ACC 2001, Late Breaking Clinical Trials, presented by David A. Kass, MD, John Hopkins Medical Institute, Baltimore, MD
Keywords: Coronary Disease, Blood Pressure, Risk Factors, Glycation End Products, Advanced, Headache, Elastin, Stroke Volume, Hypertrophy, Hypertension, Respiratory Tract Infections, Myocardial Infarction, Atherosclerosis, Pulse Wave Analysis, Diarrhea, Breast Neoplasms, Dilatation, Compliance, Echocardiography, Doppler, Chest Pain, Heart Failure, Collagen, Heart Ventricles, Lung Neoplasms, Diabetes Mellitus
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