George L. Bakris

Pathogenesis of Atherosclerotic Vascular Disease

Epidemiological studies have identified risk factors for coronary heart disease (CHD) and its underlying pathology: atherosclerosis. Genetic and environmental factors interact to shape an individual’s age-related risk of atherosclerosis (1,2). In the Framingham Heart Study, substantial proportion of the variability in carotid intima-media thickness (IMT) is explained by genetic factors (3). The role of gene polymorphism has been reviewed in ref. 4.

[OP.7A.02] SUSTAINED REDUCTION OF BLOOD PRESSURE WITH BARORECEPTOR ACTIVATION THERAPY: RESULTS OF SIX-YEAR OPEN FOLLOW-UP

Objective: Baroreflex Activation Therapy (BAT) is a novel technique for treating patients with resistant hypertension. Although short-term studies have demonstrated that BAT lowers blood pressure, long-term results have not yet been reported. The aim of the present study is to assess the long-term efficacy and safety of BAT. Design and method: Long-term follow-up data on blood pressure and heart rate were analyzed from all patients who have been included in one of the three BAT trials that focused on treatment-resistant hypertensive patients. These trials were the US feasibility study, the DEBut-HT trial and the pivotal trial. The first two were non-randomized, observational trials in the US and Europe respectively. In the pivotal trial patients were randomized to either immediate BAT or deferred BAT (six months after implantation). All patients who have received an implant were followed with regular visits. Results: Altogether, 383 patients were available for analysis: 143 of these had completed five years of follow-up and 48 patients had completed six years of follow-up. In the entire cohort, systolic blood pressure fell from 179+24 mmHg to 144+28 mmHg (p < 0.0001) while diastolic pressure dropped from 103+16 mmHg to 85+18 mmHg (p < 0.0001). The data further demonstrate that the greatest fall in pressure already occurs within 6 months following device implant. The blood pressure lowering effect of BAT is greater than average in patients with signs of heart failure, and less than average in patients with isolated systolic hypertension. The percentage of patients in whom systolic blood pressure at the end of follow-up had fallen below 140 mmHg was greatest in those with unilateral right-sided stimulation. In about 25% of patients it was possible to reduce the number of medications from a median of 6 to a median of 3. Temporary side effects, related to either the surgical procedure or to cardiovascular instability, do occur, but they do not require specific measures and resolve over time. Conclusions: After a follow-up of 5 years, BAT is safe and maintains its efficacy for persistent reduction of blood pressure in patients with resistant hypertension.

[OP.7D.01] SAFETY AND BLOOD PRESSURE EFFECTS OF SECOND- VERSUS FIRST-GENERATION SYSTEM FOR ADMINISTERING BAROREFLEX ACTIVATION THERAPY.

Objective: To compare safety and blood pressure (BP) reductions obtained with first- and second-generation systems for administering baroreflex activation therapy (BAT) in patients with resistant hypertension, as well as to verify that BP reductions with active BAT are distinguishable from placebo and Hawthorne effects observed with sham control. Design and method: Second-generation data were available from 30 patients implanted in a single-arm verification study. For comparison, datasets for two groups of 30 first-generation patients were generated by propensity-matching demographic characteristics with patients who participated in a randomized, controlled trial. These patients had been assigned to either 12 months of active BAT or 6 months of inactive BAT followed by 6 months of active BAT (sham control). Using these cohorts, safety and BP reductions were compared for the first- and second-generation BAT systems. Results: Propensity-matching produced baseline characteristics that were statistically indistinguishable between the second-generation and first-generation cohorts. BP reductions over 12 months were comparable between second-generation patients and first-generation patients assigned to active therapy. Average BP reduction for second-generation patients through 12 months was 25 ± 3 mmHg (mean ± SE, p < 0.001), with 47% of patients reaching a systolic BP < 140 mmHg. Relative to sham control, second-generation patients exhibited an additional BP reduction at 6 months of 20 ± 7 mmHg (p = 0.008), while results at 12 months were comparable. Safety of the second-generation system was superior in terms of procedure time, complications and pulse generator lifetime. Figure. No caption available. Conclusions: First- and second-generation BAT systems provide comparable BP reductions in matched populations. The treatment effect of the second-generation BAT system is significantly greater than the placebo/Hawthorne effect observed in sham controls. Second-generation system safety is improved by a minimally-invasive implant procedure and a longer lasting pulse generator.

20. Major Cardiovascular Outcomes in the EXAMINE Trial According to ACE Inhibitor Use (12-OR)

SamenvattingActivation of the sympathetic nervous system through substance P via DPP-4 inhibition (DPP-4i) in the presence of higher dose ACE inhibition (ACEi) has led to hypothetical concerns of the cardiovascular (CV) safety of these 2 classes of drugs used together. We evaluated adjudicated CV events in EXAMINE, a trial of patients with type 2 diabetes (T2DM) and recent acute coronary syndrome (ACS) according to ACEi use. Patients were randomly assigned to receive alogliptin or placebo added to existing anti-hyperglycemic and CV therapies. Risks of CV death, nonfatal MI and stroke (MACE), and CV death or hospitalized HF (HHF) were analyzed using a Cox proportional hazards model in patients by baseline ACEi use. EXAMINE random ized 5380 patients, 3323 (62%) of whom were using an ACE inhibitor (1681 on alogliptin; 1642 on placebo). Composite rates of MACE were similar for alogliptin vs. placebo with ACEi [11.4% vs. 11.8%, HR = 0.97, 95% CI, 0.79-1.19, p = 0.76] and without ACEi use at baseline [11.2% vs. 11.9%, HR = 0.94, 95% CI, 0.73-1.21, p = 0.62]. The composite of CV death or HHF in patients on ACEi at baseline occurred in 6.8% of patients on alogliptin vs. 7.2% on placebo [HR = 0.93, 95% CI, 0.72-1.2, p = 0.57]. Alogliptin showed no effect on HHF alone in ACEi treated patients, 3.3% vs. 3.1%, (HR = 1.07, 95% CI, 0.73-1.56, p = 0.75) for alogliptin vs. placebo, respectively. Additionally, there was no impact of higher vs. lower doses of ACEi on CV event rates. There were also no differences for these endpoints in patients without ACEi use at baseline. Analyses according to pre-randomization history of HF and ACEi use at baseline showed MACE occurring in 13.9% and 16.5% of patients on alogliptin vs. placebo, respectively [HR = 0.87, 95% CI, 0.63-1.19, p = 0.38] and CV death or HHF in 12.0% and 13.2% of patients on alogliptin vs. placebo, respectively [HR = 1.02, 95% CI, 0.72-1.44, p = 0.92]. In conclusion, CV outcomes were not different for alogliptin compared with placebo in high CV risk patients with T2DM treated with ACE inhibitors in the EXAMINE Trial.

Microalbuminuria and Chronic Kidney Disease as Cardiovascular Risk Factors

Retrospective analyses of data from outcome trial and large databases demonstrate that presence of either microalbuminuria (MA) or a glomerular filtration rate (GFR) below 60 ml per min is associated with an increased risk for cardiovascular (CV) events such as stroke or myocardial infarction. Presence of microalbuminuria does not imply presence of kidney disease although a GFR below 60 ml per min generally has some degree of albuminuria associated with its presence. The mechanisms proposed for the increased CV risk associated with MA are numerous. They range from increases in vascular oxidant stress associated with underlying causes of inflammation such as atherosclerosis to increases in advanced glycation products as seen in diabetes. Monitoring for MA is useful as it may uncover an inflammatory condition not otherwise appreciated as it has been shown to be better than c-reactive protein as a prediction of CV mortality in many studies. Reduced kidney function is a risk factor for higher CV event rates. The mechanisms posited for this interaction are far less clear and range from reductions in nitric oxide production secondary to an enzyme deficiency to increases in factors associated with atherosclerosis such as homocysteine. None of the factors proposed alone explains the risk, thus it is unclear. However, aggressive daily dialysis and transplantation markedly lower CV risk in those individuals. We conclude that aggressive screening for both MA and CKD be undertaken in clinical practice and that physicians aggressively seek to achieve recommended CV risk reduction guideline goals to reduce the risk of nephropathy progression.

A large-scale ambulatory blood pressure monitoring (ABPM) trial in the practice setting: efficacy of the angiotensin receptor blocker, telmisartan

Abstract P-76 Key Words: Ambulatory Blood Pressure Monitoring, Angiotensin Receptor Blocker, Hypertension