Scott J. Denardo

Tight Blood Pressure Control and Cardiovascular Outcomes Among Hypertensive Patients With Diabetes and Coronary Artery Disease

CONTEXT Hypertension guidelines advocate treating systolic blood pressure (BP) to less than 130 mm Hg for patients with diabetes mellitus; however, data are lacking for the growing population who also have coronary artery disease (CAD). OBJECTIVE To determine the association of systolic BP control achieved and adverse cardiovascular outcomes in a cohort of patients with diabetes and CAD. DESIGN, SETTING, AND PATIENTS Observational subgroup analysis of 6400 of the 22,576 participants in the International Verapamil SR-Trandolapril Study (INVEST). For this analysis, participants were at least 50 years old and had diabetes and CAD. Participants were recruited between September 1997 and December 2000 from 862 sites in 14 countries and were followed up through March 2003 with an extended follow-up through August 2008 through the National Death Index for US participants. INTERVENTION Patients received first-line treatment of either a calcium antagonist or beta-blocker followed by angiotensin-converting enzyme inhibitor, a diuretic, or both to achieve systolic BP of less than 130 and diastolic BP of less than 85 mm Hg. Patients were categorized as having tight control if they could maintain their systolic BP at less than 130 mm Hg; usual control if it ranged from 130 mm Hg to less than 140 mm Hg; and uncontrolled if it was 140 mm Hg or higher. MAIN OUTCOME MEASURES Adverse cardiovascular outcomes, including the primary outcomes which was the first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS During 16,893 patient-years of follow-up, 286 patients (12.7%) who maintained tight control, 249 (12.6%) who had usual control, and 431 (19.8%) who had uncontrolled systolic BP experienced a primary outcome event. Patients in the usual-control group had a cardiovascular event rate of 12.6% vs a 19.8% event rate for those in the uncontrolled group (adjusted hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.25-1.71; P < .001). However, little difference existed between those with usual control and those with tight control. Their respective event rates were 12.6% vs 12.7% (adjusted HR, 1.11; 95% CI, 0.93-1.32; P = .24). The all-cause mortality rate was 11.0% in the tight-control group vs 10.2% in the usual-control group (adjusted HR, 1.20; 95% CI, 0.99-1.45; P = .06); however, when extended follow-up was included, risk of all-cause mortality was 22.8% in the tight control vs 21.8% in the usual control group (adjusted HR, 1.15; 95% CI, 1.01-1.32; P = .04). CONCLUSION Tight control of systolic BP among patients with diabetes and CAD was not associated with improved cardiovascular outcomes compared with usual control. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00133692.

Effects of Arterial Stiffness, Pulse Wave Velocity, and Wave Reflections on the Central Aortic Pressure Waveform

Brachial systolic and pulse blood pressures (BPs) are better predictors of adverse cardiovascular (CV) events than diastolic BP in individuals older than 50 years. The principal cause of increased systolic and pulse BP is increased stiffness of the elastic arteries as a result of degeneration and hyperplasia of the arterial wall. Recent studies have shown that central BP, the pressure exerted on the heart, brain, and kidneys, is a better predictor of CV risk than brachial BP. As stiffness increases, reflected wave amplitude increases and augments pressure in late systole, producing an increase in left ventricular afterload and myocardial oxygen demand. Vasoactive drugs have little direct effect on large human elastic arteries but can markedly modify wave reflection by altering stiffness of the muscular arteries and changing pulse wave velocity of the reflected wave from the periphery to the heart. Vasodilators decrease the amplitude and increase the travel time (or delay) of the reflected wave, causing a generalized decrease in systolic BP. The decrease in systolic BP brought about by this mechanism is grossly underestimated when systolic BP is measured in the brachial artery.

Blood pressure and outcomes in very old hypertensive coronary artery disease patients: an INVEST substudy.

BACKGROUND Our understanding of the growing population of very old patients (aged >or=80 years) with coronary artery disease and hypertension is limited, particularly the relationship between blood pressure and adverse outcomes. METHODS This was a secondary analysis of the INternational VErapamil SR-Trandolapril STudy (INVEST), which involved 22,576 clinically stable hypertensive coronary artery disease patients aged >or=50 years. The patients were grouped by age in 10-year increments (aged >or=80, n=2180; 70-<80, n=6126; 60-<70, n=7602; <60, n=6668). Patients were randomized to either verapamil SR- or atenolol-based treatment strategies, and primary outcome was first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS At baseline, increasing age was associated with higher systolic blood pressure, lower diastolic blood pressure, and wider pulse pressure (P <.001). Treatment decreased systolic, diastolic, and pulse pressure for each age group. However, the very old retained the widest pulse pressure and the highest proportion (23.6%) with primary outcome. The adjusted hazard ratio for primary outcomes showed a J-shaped relationship among each age group with on-treatment systolic and diastolic pressures. The systolic pressure at the hazard ratio nadir increased with increasing age, highest for the very old (140 mm Hg). However, diastolic pressure at the hazard ratio nadir was only somewhat lower for the very old (70 mm Hg). Results were independent of treatment strategy. CONCLUSION Optimal management of hypertension in very old coronary artery disease patients may involve targeting specific systolic and diastolic blood pressures that are higher and somewhat lower, respectively, compared with other age groups.

Outcomes Among Hypertensive Patients With Concomitant Peripheral and Coronary Artery Disease: Findings From the INternational VErapamil-SR/Trandolapril STudy

Hypertension is a common risk factor for peripheral arterial disease (PAD). Guidelines suggest treating PAD patients to a blood pressure <130/80 mm Hg; therefore, our objective was to explore whether attainment of this target blood pressure is associated with improved outcomes. We performed a post hoc analysis of the INternational VErapamil-SR/Trandolapril STudy, a randomized clinical trial, which included hypertensive patients with concomitant PAD and coronary artery disease. There were 2699 PAD patients followed for a mean of 2.7 years (60 970 patient-years). The primary outcome, all-cause death, nonfatal myocardial infarction, or nonfatal stroke, occurred in 16.3% of PAD patients versus 9.2% without PAD (adjusted hazard ratio: 1.26 [95% CI: 1.13 to 1.40]; P<0.0001). The primary outcome occurred least frequently among PAD patients treated to an average systolic blood pressure of 135 to 145 mm Hg and an average diastolic blood pressure of 60 to 90 mm Hg. PAD patients displayed a J-shape relationship with systolic blood pressure and the primary outcome, although individuals without PAD did not. PAD patients may require a different target blood pressure than those without PAD.

Pulse Wave Analysis of the Aortic Pressure Waveform in Severe Left Ventricular Systolic Dysfunction

Background—The effect of moderate left ventricular systolic dysfunction (LVSD) on ventricular/vascular coupling and the aortic pressure waveform (AoPW) has been well described, but the effect of severe LVSD has not. Methods and Results—We used noninvasive, high-fidelity tonometry of the radial artery and a mathematical transfer function to generate the AoPW in 25 treated patients with LVSD (mean LV ejection fraction, 24±8.8%; range, 11% to 40%; 21 patients <30%). Pulse wave analysis of the AoPW was used to characterize ventricular/vascular coupling and compared with pulse wave analysis performed in 25 normal subjects matched for age, gender, height, body mass index, and heart rate. Measurements obtained using pulse wave analysis in LVSD patients indicated features of poor LV stroke performance and also reduced indices of arterial stiffness: increased travel time of the pressure wave (147±10 ms versus 132±21 ms; P<0.001); decreased systolic duration of reflected wave (134±24 ms versus 167±26 ms; P<0.001); ejection duration (277±22 ms versus 299±25 ms; P<0.008); percent systolic duration (32±5.3% versus 35±4.0%; P<0.02); aortic systolic pressure (100±16 mm Hg versus 121±16 mm Hg; P<0.001); unaugmented pressure (24±6.3 mm Hg versus 32±6.4 mm Hg; P<0.001); augmented pressure (4.8±3.1 mm Hg versus 9.6±4.5 mm Hg; P<0.001); pulse pressure (28±7.4 mm Hg versus 42±9.5 mm Hg; P<0.001); augmentation index (12±6.6% versus 23±7.6%; P<0.006); wasted LV effort (5.3±2.8×102 dyne sec/cm2 versus 17±10×102 dyne sec/cm2; P<0.001); systolic pressure time index (17±4.1×102 mm Hg-sec/min versus 23±4.2×102 mm Hg sec/min; P<0.001); and pressure systolic area (383±121 mm Hg sec/min versus 666±150 mm Hg sec/min; P<0.001). Conclusions—Severe LVSD causes measurable changes in the AoPW. Standardization of AoPW findings in LVSD patients may allow for the clinical use of radial artery pulse wave analysis to noninvasively determine the severity of dysfunction and aid in logical therapy.

Coronary Revascularization Strategy and Outcomes According to Blood Pressure (from the International Verapamil SR-Trandolapril Study [INVEST])

The optimal blood pressure (BP) to prevent major adverse outcomes (death, myocardial infarction, and stroke) for patients with hypertension and coronary artery disease who have undergone previous revascularization is unknown but might be influenced by the type of revascularization procedure. We analyzed data from the INternational VErapamil SR-Trandolapril STudy, focusing on the relation between BP and the outcomes of 6,166 previously revascularized patients, using the 16,410 nonrevascularized patients as a reference group. The previous revascularization strategy consisted of coronary artery bypass grafting (CABG, 45.2%), percutaneous coronary intervention (PCI, 42.1%), or both (CABG+PCI, 12.8%). Patients who had undergone both CABG+PCI and CABG-only had a greater adverse outcome risk (adjusted hazard ratio 1.27% and 1.20%, 95% confidence interval 1.06 to 1.53 and 1.07 to 1.35, respectively). The risk was similar for PCI-only patients (adjusted hazard ratio 1.04, 95% confidence interval 0.92 to 1.19). The relations between the adjusted hazard ratio and on-treatment BP appeared J-shaped for each revascularization strategy, accentuated for PCI and diastolic BP (DBP), but excepting CABG only and DBP for which the relation was linear and positive. In conclusion, major adverse outcomes were more frequent in patients with coronary artery disease who had undergone previous CABG, with or without PCI, compared to those with previous PCI only. This likely reflected more severe vascular disease. The relation to systolic BP was J-shaped for each strategy. Among those patients with previous CABG only, the linear relation with DBP suggested that more complete revascularization might attenuate hypoperfusion at a low DBP. The management of BP might, therefore, require modification of targets according to the revascularization strategy to improve outcomes.

Effect of Phosphodiesterase Type 5 Inhibition on Microvascular Coronary Dysfunction in Women: A Women’s Ischemia Syndrome Evaluation (WISE) Ancillary Study

Microvascular coronary dysfunction (MCD) is associated with symptoms and signs of ischemia, and also adverse outcomes in women without macrovascular obstructive coronary artery disease (M‐CAD). Although MCD can be quantified using coronary flow reserve (CFR), treatment is poorly defined.

Changes to Polymer Surface of Drug-Eluting Stents During Balloon Expansion

Form for Disclosure of Potential Conflicts of Interest and reported being a member of the board of directors of the American Social Health Association; receiving payment from the American Social Health Association for developing educational materials on HPV prevention through an unrestricted grant to the association from Merck; recently completing a term as a member of Merck’s Gardasil Male Population Advisory Committee; and receiving royalties from McGraw-Hill for his book, Color Atlas and Synopsis of Sexually Transmitted Diseases, 2nd and 3rd editions.

Increased wave reflection and ejection duration in women with chest pain and nonobstructive coronary artery disease: ancillary study from the Women's Ischemia Syndrome Evaluation.

Objective: Wave reflections augment central aortic SBP and increase systolic pressure time integral (SPTI) thereby increasing left ventricular (LV) afterload and myocardial oxygen (MVO2) demand. When increased, such changes may contribute to myocardial ischemia and angina pectoris, especially when aortic diastolic time is decreased and myocardial perfusion pressure jeopardized. Accordingly, we examined pulse wave reflection characteristics and diastolic timing in a subgroup of women with chest pain (Womens Ischemia Syndrome Evaluation, WISE) and no obstructive coronary artery disease (CAD). Methods: Radial artery BP waveforms were recorded by applanation tonometry, and aortic BP waveforms derived. Data from WISE participants were compared with data from asymptomatic women (reference group) without chest pain matched for age, height, BMI, mean arterial BP, and heart rate. Results: Compared with the reference group, WISE participants had higher aortic SBP and pulse BP and ejection duration. These differences were associated with increased augmentation index and reflected pressure wave systolic duration. These modifications in wave reflection characteristics were associated with increased SPTI and wasted LV energy (Ew) and a decrease in pulse pressure amplification, myocardial viability ratio, and diastolic pressure time fraction. Conclusion: WISE participants with no obstructive CAD have changes in systolic wave reflections and diastolic timing that increase LV afterload, MVO2 demand, and Ew with the potential to reduce coronary artery perfusion. These alterations in cardiovascular function contribute to an undesirable mismatch in the MVO2 supply/demand that promotes ischemia and chest pain and may contribute to, or increase the severity of, future adverse cardiovascular events.

Characteristics and Outcomes of Revascularized Patients With Hypertension. An International Verapamil SR-Trandolapril Substudy

Our understanding of the growing population of revascularized patients with hypertension is limited. We retrospectively analyzed the International Verapamil SR-Trandolapril Study, which randomized coronary artery disease patients with hypertension to either verapamil SR- or atenolol-based treatment strategies, focusing on characteristics and outcomes of 6166 previously revascularized patients compared with 16 410 nonrevascularized patients. Revascularized patients had a history of coronary artery bypass grafting (45.2%), percutaneous coronary intervention (42.1%), or both (12.8%). Compared with nonrevascularized patients, revascularized patients at baseline demonstrated a higher prevalence of coronary artery disease risk factors and risk conditions (P<0.001). This higher prevalence was the principal cause of a higher incidence of primary outcome (death, nonfatal myocardial infarction, or nonfatal stroke) among revascularized patients (14.2% versus 8.5% for nonrevascularized patients; P<0.001). However, both patient groups demonstrated a relatively low incidence of subsequent revascularization (5.1% versus 1.5% respectively; P<0.0001). Associations between adjusted hazard ratio for primary outcome and follow-up blood pressure appeared “J shaped” for both patient groups. Because, as a group, revascularized patients with hypertension had worse outcomes compared with nonrevascularized patients, management of blood pressure to a specific target in future studies could result in improved outcomes.