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The funding information in this paper was presented incorrectly. It should be: This study was supported in part by Aegerion, Inc. and REGENXBIO Inc.

Statin-associated muscle symptoms are reported by 10% to 29% of patients in clinical practice and are a major determinant of statin nonadherence, discontinuation, and switching. Little is known about what advice patients receive from their providers when dealing with these symptoms.The objective of the study was to assess patient's reports of provider advice when experiencing new or worsened muscle symptoms while taking a statin.Data were analyzed from the Understanding Statin Use in America and Gaps in Education survey, a self-administered internet-based survey of 10,138 adults with a reported history of high cholesterol and statin use.Of the respondents, 60% of former statin users (n = 1220) reported ever experiencing new or worsened muscle pain on a statin, in contrast to 25% of current users (n = 8918; P .001). Former statin users reported stopping more statins because of muscle symptoms (mean ± standard deviation, 2.2 ± 1.7) compared with current users (mean 1.6 ± 1.5, P .0001). For those with muscle-related symptoms while on a statin, participants reported that providers most often suggested switching to another statin (33.8%), stopping the statin (15.9%), continuing the statin with further monitoring of muscle symptoms (12.2%), reducing the statin dose (9.8%), or getting a blood test for signs of muscle damage (9.2%). A lower percentage were advised to add either vitamin D (7.0%) or coenzyme Q10 (5.8%), or to switch to nonstatin therapy (6.1%) or red yeast rice (2.6%).This study highlights patient experience with statin-associated muscle symptoms and the strategies recommended by providers in managing these symptoms. More research is needed to develop patient-centric and evidence-based approaches to managing statin-associated muscle symptoms, which is especially important in light of recent data showing increased cardiovascular risk among those who discontinue statin therapy.

It is important to understand patients' experiences of statin-associated adverse effects to potentially identify those at risk for stopping treatment.The goal of the STatin Adverse Treatment Experience survey was to describe patients' experiences after reporting ≥1 recent statin-associated adverse event and identify opportunities to improve adherence and outcomes.The survey was developed in 3 stages: qualitative item development, pilot evaluation of initial item performance, and quantitative evaluation using a large commercial sample. Respondents with self-reported high cholesterol who had taken a statin in the past 2 years and experienced ≥1 statin-associated symptom in the past 6 months were included (N = 1500).Mean age was 58 years, 40.3% were men, and 43.2% had tried ≥2 statins. Many had clinical comorbidities associated with increased risk for cardiovascular disease (atherosclerotic cardiovascular disease, 22.5%; diabetes, 25.8%; hypertension, 56.0%). The most important patient-reported reasons for continuing current statin therapy (n = 1168; 77.9%) were avoiding a heart attack or stroke, lowering cholesterol, and doctor recommendation. Being bothered by and not being able to tolerate side effects were the main reasons respondents discontinued statins (n = 332; 22.1%). Respondents who discontinued statins reported significantly higher mean Symptom Severity (10.6 vs 8.7, P .001) and Impact Severity scores (11.8 vs 9.8, P .001) compared with those who continued.The STatin Adverse Treatment Experience survey highlights the importance of patients' adverse experiences with statins and how symptom and impact scores affect decisions to continue or discontinue therapy. These data provide a foundation to increase providers' awareness of statin tolerability from the patient's perspective and encourage benefit-risk discussions.

Background Statin therapy is recommended for reducing atherosclerotic cardiovascular disease (ASCVD) risk. Significant risk can remain because of insufficient clinical response or statin intolerance. Proprotein convertase subtilisin/kexin type-9 (PCSK9) therapy lowers low-density lipoprotein cholesterol and has recently been shown to lower ASCVD events. Objective The aim of the study was to assess the barriers and challenges experienced with the access and approval reimbursement process for PCSK9 inhibitor prescriptions. Methods In 2016, the National Lipid Association conducted an online survey on PCSK9 inhibitor use and barriers to prescription among experienced healthcare workers who provide care to high-risk patients with ASCVD or familial hypercholesterolemia (FH). Results There were 434 respondent healthcare workers with extensive experience in treating lipid disorders. PCSK9 inhibitors are considered by 71.3% of respondent providers with statin-intolerant patients. There were high rates (>85%) of initial denial. The major barriers to approvals were insurer processes, provider documentation (inadequate documentation of maximally tolerated statin dose, diagnostic criteria for FH, number of statins failed if statin intolerant and most recent low-density lipoprotein cholesterol), and administrative burden (time, staff, paperwork, and appeals). Provider approval rates for getting ≥75% patients approved were higher for FH (43%) than for ASCVD patients (36%). Among providers with good approval rates, documentation was the most critical factor. Barriers more difficult to overcome include perceived higher threshold requirements by payers, drugs not on formulary, and drug costs. Conclusions Healthcare providers encounter significant barriers to PCSK9 inhibitor prescriptions; many of these are related to documentation issues and can be overcome with checklists, staff support, and experience.

Drug interactions have been identified as a risk factor for muscle-related side effects in statin users.The aim was to assess whether use of medications that inhibit cytochrome P450 (CYP450) isozymes, organic anion transporting polypeptide 1B1 (OATP1B1), or P-glycoprotein (P-gp) are associated with muscle-related symptoms among current and former statin users.Persons (n = 10,138) from the Understanding Statin Use in America and Gaps in Education (USAGE) internet survey were categorized about whether they ever reported new or worsening muscle pain while taking a statin (n = 2935) or ever stopped a statin because of muscle pain (n = 1516). Univariate and multivariate logistic regression models were used to assess associations between use of concomitant therapies that inhibit CYP450 isozymes, OATP1B1, P-gp, or a combination and muscle-related outcomes.In multivariate analyses, concomitant use of a CYP450 inhibitor was associated with increased odds for new or worse muscle pain (odds ratio [OR] = 1.42; P.001) or ever having stopped a statin because of muscle pain (OR = 1.28; P = .037). Concomitant use of medication known to inhibit both OATP1B1 and P-gp was also associated with increased odds (OR = 1.80; P = .030) of ever having stopped a statin because of muscle pain.Concomitant use of medication(s) that inhibit statin metabolism was associated with increased odds of new or worse muscle pain while taking a statin and having previously stopped a statin because of muscle symptoms. These data emphasize the importance of enhancing the capabilities of clinicians and health systems for identifying and reducing statin drug interactions.

Background Large gaps in lipid treatment and medication adherence persist in high-risk outpatients in the United States. Health information technology (HIT) is being applied to close quality gaps in chronic illness care, but its utility for lipid management has not been widely studied. Objective To perform a qualitative review of the impact of HIT interventions on lipid management processes of care (screening or testing; drug initiation, titration or adherence; or referrals) or clinical outcomes (percent at low density lipoprotein cholesterol goal; absolute lipid levels; absolute risk scores; or cardiac hospitalizations) in outpatients with coronary heart disease or at increased risk. Methods PubMed and Google Scholar databases were searched using Medical Subject Headings related to clinical informatics and cholesterol or lipid management. English language articles that described a randomized controlled design, tested at least one HIT tool in high risk outpatients, and reported at least 1 lipid management process measure or clinical outcome, were included. Results Thirty-four studies that enrolled 87,874 persons were identified. Study ratings, outcomes, and magnitude of effects varied widely. Twenty-three trials reported a significant positive effect from a HIT tool on lipid management, but only 14 showed evidence that HIT interventions improve clinical outcomes. There was mixed evidence that provider-level computerized decision support improves outcomes. There was more evidence in support of patient-level tools that provide connectivity to the healthcare system, as well as system-level interventions that involve database monitoring and outreach by centralized care teams. Conclusion Randomized controlled trials show wide variability in the effects of HIT on lipid management outcomes. Evidence suggests that multilevel HIT approaches that target not only providers but include patients and systems approaches will be needed to improve lipid treatment, adherence and quality.

Background Although statins have been shown to reduce cardiovascular disease mortality, less than half of U.S. adults achieve their low-density lipoprotein cholesterol goal. In many patients initiated on a statin, adherence rates decrease over time. Objective To characterize current and former statin users, identify reasons for the discontinuation or switching of statins, and identify factors associated with adherence. Methods The USAGE survey is a cross-sectional, self-administered Internet-based survey of 10,138 U.S. adults fielded September to October 2011. The following statin users were identified and compared: adherent nonswitchers, adherent switchers, non-adherent switchers, and discontinuers. Univariate and multivariate models using a priori covariates for adherence and discontinuation were examined. Results Most participants were current statin users who adhered with their prescribed statin (82.5%, n = 8371). Former statin users or discontinuers (12%, n = 1220) cited muscle pain, a side effect, as the primary reason for discontinuation (60%), followed by cost (16%), and then perceived lack of efficacy (13%). Discontinuers were less satisfied with their physicians' explanation of cholesterol treatment, more likely to use the Internet to research statins, and less likely to undergo frequent cholesterol monitoring. Among adherent statin users, the primary reasons for switching were muscle side effects (33%) and cost (32%). Individuals at risk for non-adherence included those with low household income, those who experienced muscle pain as a side effect while on statin therapy, and those taking medication for cardiovascular disease. Conclusion Statin-related muscle side effects are common and contribute significantly to rates of discontinuation, switching, and non-adherence. Improved physician patient communication about side effects and benefits of statins are necessary to improve both adherence and outcomes.

Statins substantially reduce the risk of cardiovascular disease and are generally well-tolerated. Despite this, many patients discontinue therapy. A better understanding of the characteristics of current and former statin users may be helpful for formulating strategies to improve long-term adherence.The Understanding Statin Use in America and Gaps in Education (USAGE) survey assessed the attitudes, beliefs, practices, and behavior of current and former statin users.Individuals 18 years or older who reported a history of high cholesterol and current or former statin use were identified within a registered consumer panel cohort in the United States and invited to participate in an Internet survey.Of the 10,138 respondents, 8918 (88%) were current statin users and 1220 (12%) were former users. Participants (mean age 61 years) were predominantly white (92%), female (61%), of middle income (median $44,504/yr), and had health insurance (93%). Among current users, 95% took a statin alone, and 70% had not missed a dose in the past month. Although ∼70% reported that their physicians had explained the importance of cholesterol levels for their heart health former users were less satisfied with the discussions (65% vs. 83%, P.05). Muscle-related side effects were reported by 60% and 25% of former and current users, respectively (P.05). Nearly half of all respondents switched statins at least once. The primary reason for switching by current users was cost (32%) and the primary reason for discontinuation was side effects (62%).This survey provides important insights into behavior and attitudes among current and former statin users and the results suggest that more effective dialogue between healthcare providers and patients may increase persistence of statin use, particularly when the patient has concerns about side effects and drug costs.

Statin therapy has been shown to reduce cardiovascular morbidity and mortality, and the benefits of statin therapy are similar for men and women. Recent studies have shown that women are less likely to be treated with statin therapy, to be on higher doses of more potent statins, and to achieve their lipid goals as compared with men.To analyze results from the Understanding Statin Use in America and Gaps in Patient Education (USAGE) survey and to assess whether women differ from men with regard to reported side effects associated with statin use, clinician and patient interactions, as well as general attitudes and preferences regarding statin use.The study population was derived from participants in the USAGE survey, a self-administered, Internet-based questionnaire.More women reported switching or stopping a statin because of side effects compared with men. New or worsening muscle symptoms were reported in 31% of women compared with 26% of men (P .01). More women, including high-risk women reported that their doctor did not give them information about their risk for heart disease compared with men. Women were more likely to try 3 or more statins, but less likely to use alternative low-density lipoprotein cholesterol-lowering drugs. Women were more likely to be dissatisfied with their statin, with how their clinician explained their cholesterol treatment, and less adherent to their statin than men.Women are more likely to stop or switch their statin than men, and the main reason for this was new or worsening muscle symptoms. Improved communication between the clinician and the patient about the benefits and risks of statin therapy will improve adherence, lipid goal attainment, and outcomes in women with or at risk for cardiovascular disease.

We tested the hypotheses whether nuclear magnetic resonance (NMR) determined lipoprotein particles, insulin and adiponectin, and C-reactive protein (CRP) and white blood cell (WBC) count as markers of inflammation predicted risk of coronary heart disease (CHD) death among 428 men age 35-57 years with metabolic syndrome (MetSyn) in a matched case control study within the multiple risk factor intervention trial. Blood samples collected at entry into the study and stored at -60 degrees C were obtained from central storage for blood analyte analysis. Two hundred and fourteen men with MetSyn who died of CHD were matched with 214 men with MetSyn who did not die of CHD during 18 years of follow-up. Cases were matched to controls on age, study group, number of factors present in the MetSyn, and presence or absence of a nonfatal CVD event during the trial. Mortality follow-up was determined using the National Death Index. Higher levels of high density lipoprotein particles (HDL-P), especially medium-sized HDL-P [hazard ratio (95% confidence interval) 0.45 (0.25-0.83, P

Surveys commissioned by the National Lipid Association (NLA) were conducted to determine the current attitudes and perceptions of physicians, consumers, and pharmacists regarding the impact of an over-the-counter (OTC) statin. Individuals from preexisting independent databases were randomly invited to participate in the online surveys that were open from January 26 to 30, 2004 for physicians and consumers and from March 1 to 12, 2004 for pharmacists. The results of these surveys indicate that consumers and pharmacists are more positive regarding the idea of an OTC statin, whereas physicians are more guarded. Concerns of both physicians and pharmacists included the discontinuation by patients of their prescription cholesterol-lowering therapy without consulting their physician, safety issues such as potential drug interactions and side effects, and patient ability to self-manage OTC statins. Consumers interested in purchasing an OTC statin reported that they would consult their physician before doing so, and pharmacists were interested in supporting consumers who use OTC statins. Although such support would require further training and time, pharmacists believed that they could facilitate consumer self-care programs and follow-up with physicians.

Background: Despite a high prevalence of hypertension in the population with CAD, there are limited data describing the clinical characteristics and treatments, as well as their interrelations in these patients. This is particularly true for black and Hispanic patients who have been underrepresented in randomized CAD trials. Hypothesis: There exist racial and ethnic differences that define the characteristics of patients with both coronary artery disease (CAD) and hypertension. Methods: This report describes the characteristics of Caucasian, Hispanic, and black patients enrolled in the International Verapamil SR/trandolapril Study (INVEST), a prospective trial undertaken exclusively in patients with CAD and hypertension. Results: In all, 10,925 Caucasian, 8,045 Hispanic, and 3,029 black patients are described. An abnormal angiogram or documented myocardial infarction was observed more frequently in Caucasian patients (73%), while angina pectoris was more prevalent in Hispanic patients (87%). Diabetes and left ventricular hypertrophy were most common in black patients (33 and 29%, respectively), while hypercholesterolemia and prior revascularization (coronary artery bypass graft or angioplasty) were most common in Caucasian patients (64 and 41%, respectively). More than 60% of Hispanic and black patients were women—a unique characteristic for randomized CAD trials. Comparing race/ethnic cohorts, there were significant differences for all characteristics. More than 80% of patients in all race/ethnic groups were receiving antihypertensive therapy; however, only fewer than 25% had controlled blood pressure according to guidelines from the sixth report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Conclusions: This high-risk population of hypertensive patients with CAD has been undertreated and does not have well-controlled B P. Race/ethnic differences were observed for clinical characteristics and medication use.

Background: Testing for troponin has important clinical value for patients who present with typical symptoms of acute coronary syndromes (ACS) such as chest pain (CP). Much less is known about the value of troponin testing for patients who present with other symptoms of ACS (anginal equivalent symptoms).Methods: The utilization and prognostic value of cardiac troponin I (cTnI) were evaluated at a Veterans Affairs Acute Care Facility. Clinical charts of 1184 predominantly male patients, who submitted specimens for initial cTnI testing by AxSYM, were evaluated for demographic data, cardiovascular risk factors, major diseases, and complaints at the time of testing. The endpoint was defined as all-cause death during a 200-day period after initial testing.Results: Sixty-one percent of cTnI tests were ordered for patients who did not present with CP. Patients presenting with symptoms other than CP did not have significantly lower plasma cTnI than patients with CP. However, patients with symptoms other than CP were rarely diagnosed with ACS unless cTnI was ≥2 μg/L. The mortality during the follow-up period was severalfold higher among patients presenting with symptoms other than CP (CP, 6%; without CP, 22%; P Conclusion: Patients with anginal equivalent symptoms of ACS and low-positive cTnI are less often diagnosed with ACS and have a higher mortality than patients with CP.

Background: Despite improvements in care, the prognosis for patients with congestive heart failure (CHF) remains poor. Fifty percent of patients with CHF suffer from arrhythmia and sudden cardiac death. This may be attributable in part to the use of medications that contribute to electrolyte imbalance. Objective: This article presents a case report of a woman with CHF due to left ventricular systolic dysfunction. Results: The case report involved a 52-year-old white woman with a history of paroxysmal atrial fibrillation, atypical chest pain, and dyslipidemia. Her medical treatment had included the use of furosemide (a loop diuretic), digoxin, and sotalol; she subsequently developed torsades de pointes (TdP). An electrocardiogram showed normal sinus rhythm; the QT c interval was 530 msec. Levels of digoxin, K + , and Mg 2+ were 1.8 ng/mL, 3.5 mEq/L, and 1.5 mEq/L, respectively. Results of a Holter monitor recording suggested that the hypomagnesemia and hypokalemia, interacting with the digoxin and sotalol, potentiated the development of a prolonged QT interval. To ensure the TdP did not recur, an IV bolus of Mg 2+ was administered and oral triamterene therapy was added to the patient's current medications. These additions appeared to correct the electrolyte imbalance. Conclusion: This case exemplifies the importance of recognizing and managing electrolyte imbalance in the treatment of patients with CHF.

1996;3:213–219. 5. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341: 410 –418. 6. Bloomfield Rubins H, Davenport J, Babikian V, Brass LM, Collins D, Wexler L, Wagner S, Papademetriou V, Rutan G, Robins SJ. Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). Circulation 2001;103:2828– 2833. 7. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, et al. Helsinki Heart Study: primaryprevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237–1245.

Sex differences in the pathophysiologic course of coronary artery disease (CAD) are widely recognized, yet accurate diagnosis of coronary artery disease in women remains challenging.To determine sex differences in the clinical manifestation of CAD, we studied chest pain reported during daily activities, exercise, and mental stress in 170 men and 26 women. All patients had documented CAD (50% narrowing in at least 1 major coronary artery or prior myocardial infarction) and all had 1-mm ST-segment depression on treadmill exercise. We collected psychologic test results, serum samples (potassium, epinephrine, norepinephrine, cortisol, b-endorphin, and glucose), and cardiac function, sensory threshold, and autonomic function data at specified times before, during, or after exercise and mental stress tests to assess measures of depression, anxiety, and neurohormonal and thermal pain perception.Women reported chest pain more often than men during daily activities (P =.04) and during laboratory mental stressors (P =.01) but not during exercise. Men had lower scores than women on measures of depression, trait anxiety, harm avoidance, and reward dependence (P.05 for all). Women had significantly lower plasma b-endorphin levels at rest (4.2 +/- 3.9 vs 5.0 +/- 2.5 pmol/L for men, P =.005) and at maximal mental stress (6.4 +/- 5.1 vs 7.4 +/- 3.5 pmol/L for men, P.01). A higher proportion of women than men had marked pain sensitivity to graded heat stimuli applied to skin (hot pain threshold41 degrees C, 33% vs 10%, P =.001).Our results reflect sex differences in the affective and discriminative aspects of pain perception and may help explain sex-related differences in clinical presentations.

This large multicenter study, tested the antihypertensive effects of isradipine, a dihydropyridine calcium channel blocker and enalapril, an angiotensin-converting enzyme inhibitor, in salt-sensitive hypertensive patients under low and high salt intake diets. After a 3-week (weeks − 9 to − 6) of ad lib salt diet, those patients who had a sitting diastolic blood pressure (SDBP) of ≥ 95 but ≤ 115 mm Hg qualified to enter a 3-week (weeks − 6 to − 3) placebo run-in low salt diet (50 to 80 mmol Na + /day). Then high salt (200 to 250 mmol Na + /day) was added to the placebo treatment for 3 weeks (weeks − 3 to 0). Those patients who demonstrated an increase in SDBP ≥ 5 mm Hg from the low to high salt diet were considered salt sensitive and were randomized into a 4-week (weeks 0 to 4) double-blind treatment period of either isradipine 2.5 to 10 mg twice a day, enalapril 2.5 to 20 mg twice a day, or placebo. Then they entered a 3-week (weeks 4 to 7) placebo washout phase of low salt diet (50 to 80 mmol Na + /day). After week 7 and while the low salt diet was continued the patients were restarted on their double-blind treatment for 4 more weeks (weeks 7 to 11) and the study was completed. Of 1916 patients screened, 464 were randomized into the double-blind treatment phase and 397 completed the study. Both isradipine and enalapril decreased the sitting systolic blood pressure (SSBP) and SDBP during the high salt diet, to a similar degree, whereas enalapril caused a greater reduction in SSBP and SDBP than isradipine during the low salt diet (11.3 ± 1.2/7.7 ± 0.7 mm Hg v 7.7 ± 0.9/4.8 ± 0.6 mm Hg, mean ± SEM, respectively, P .02). Within drugs, the effect of isradipine on blood pressure (BP) was higher during the high than the low salt diet (14.9 ± 1.5 v 7.6 ± 1.3 mm Hg for SSBP and 10.1 ± 0.6 v 4.8 ± 0.9 mm Hg for SDBP, P .001), but enalapril exerted a similar effect during both diets. Because salt restriction lowered both SSBP and SDBP, the lowest BP achieved with both drugs were during the salt restriction phase.

Background The favorable effects of lowering low-density lipoprotein (LDL)-cholesterol on reducing clinical events in patients with coronary disease have been well established. The mechanisms responsible for this benefit, however, have not been fully understood. This study examined the impact of lipid-lowering therapy on endothelium-dependent vasoreactivity in a subgroup of patients after myocardial infarction with average cholesterol levels who participated in the Cholesterol Recurrent Events (CARE) study to determine whether an effect on endothelial function is a viable mechanism for the observed reduction in clinical events. Methods and Results Participants were recruited from among volunteers in the CARE trial at 2 university-based outpatient cardiology clinics. Patients were randomly assigned to provastatin or placebo. Plasma lipids were measured at baseline and semiannually thereafter. During the final 6 months of the trial, vasoreactivity was assessed by change in ultrasound-determined brachial artery diameter in response to blood pressure cuff-induced ischemia (endothelium-dependent) and to nitroglycerin, a direct vasodilator. Differences in response were examined between the 2 randomized groups. The relation between change in LDL-cholesterol from baseline to year 5 and the magnitude of endothelium-dependent vasodilation also was examined. There was significantly greater endothelium-dependent vasodilation observed in the provastatin group compared with the placebo group (13% vs 8%, P = .0002), with no difference between the groups in their response to the endothelium-dependent vasodilator nitroglycerin. The magnitude of the endothelium-dependent vasodilation was significantly correlated with the percent change in LDL-cholesterol from baseline to final visit ( r = 0.49, P = .015). Conclusions These findings indicate that the use of provastatin in patients after myocardial infarction with average cholesterol levels is associated with greater endothelium-dependent vasodilation compared with those who received placebo. The magnitude of this vasodilatory response is correlated to the reduction in LDL-cholesterol. This improvement in endothelium-dependent vasoreactivity may be a likely mechanism, at least in part, for the reduction in recurrent clinical events observed and reported in the CARE study.

OBJECTIVES The purposes of this database study were to determine: 1) the relationship between mental stress–induced ischemia and ischemia during daily life and during exercise; 2) whether patients who exhibited daily life ischemia experienced greater hemodynamic and catecholamine responses to mental or physical stress than patients who did not exhibit daily life ischemia, and 3) whether patients who experienced daily life ischemia could be identified on the basis of laboratory-induced ischemia using mental or exercise stress testing. BACKGROUND The relationships between mental stress–induced ischemia in the laboratory and ischemia during daily life and during exercise are unclear. METHODS One hundred ninety-six stable patients with documented coronary disease and a positive exercise test underwent mental stress testing and bicycle exercise testing. Radionuclide ventriculography and electrocardiographic (ECG) monitoring were performed during the mental stress and bicycle tests. Patients underwent 48 h of ambulatory ECG monitoring. Hemodynamic and catecholamine responses were obtained during mental stress and bicycle tests. RESULTS Ischemia (reversible left ventricular dysfunction or ST segment depression ≥1 mm) developed in 106 of 183 patients (58%) during the mental stress test. There were no significant differences in clinical characteristics of patients with, compared with those without, mental stress–induced ischemia. Patients with mental stress ischemia more often had daily life ischemia than patients without mental stress ischemia, but their exercise tests were similar. Patients with daily life ischemia had higher ejection fraction and cardiac output, and lower systemic vascular resistance during mental stress than patients without daily life ischemia. Blood pressure and catecholamine levels at rest and during the mental stress tests were not different in patients with, compared with those without, daily life ischemia. Patients with daily life ischemia had a higher ejection fraction at rest and at peak bicycle exercise compared with patients without daily life ischemia, but there were no other differences in peak hemodynamic or catecholamine responses to exercise. The presence of ST segment depression during routine daily activities was best predicted by ST segment depression during mental or bicycle exercise stress, although ST segment depression was rare during mental stress. CONCLUSIONS Patients with daily life ischemia exhibit a heightened generalized response to mental stress. ST segment depression in response to mental or exercise stress is more predictive of ST segment depression during routine daily activities than other laboratory-based ischemic markers. Therapeutic management strategies might therefore focus on patients with these physiologic responses to stress and on whether lessening such responses reduces ischemia.

Our understanding of the process leading to hypertension is allowing us to adopt principles of therapy that may be more beneficial for patients.To review the physiology, vasular biology, and mechanisms of hypertension.Hypertension, particularly in high-risk patients, is a result of loss of balance and the absence of the ability to vasodilate normally. The interaction between the endothelial cell and the smooth muscle cell is very important in this process. The endothelium is a group of cells that produce compounds that are important in regulating vascular homeostasis by elaborating factors such as angiotensin II, nitric oxide (NO), endothelin, and prostaglandins. Specifically, NO is found in endothelial cells responsible for smooth muscle relaxation. Gaseous NO diffuses across the endothelial cell and into the underlying smooth muscle cell, where it stimulates the pathway of guanylate cyclase to produce vasorelaxation. Normal endothelium maintains vascular tone and blood viscosity, prevents abnormal blood clotting and bleeding, limits inflammation of the vasculature, and suppresses smooth muscle cell proliferation. Abnormal endothelium causes increased inflammation and hypertrophy of the smooth muscle cells, promotes thrombosis and vasoconstriction, and creates a situation ripe for establishment and rapid growth of atherosclerotic plaques. Endothelial dysfunction also predicts poor outcome in patients with non-insulin-dependent diabetes mellitus and may worsen insulin resistance, increase vascular reactivity, and encourage macrovascular disease.Understanding endothelial vasculature will be imperative as researchers develop newer compounds that may enhance NO formation within the vasculature.

The objectives of this study were to compare and contrast indicators of ischemia in a well-characterized group of 196 patients with coronary artery disease, documented angiographically or by verified history of myocardial infarction, and a positive exercise test result. Myocardial ischemia occurs frequently in response to everyday stressors in patients with coronary artery disease. The Psychophysiological Interventions in Myocardial Ischemia study provides a unique opportunity to study neuroendocrine and psychological manifestations of ischemia. Patients with exercise-induced ischemia underwent exercise radionuclide ventriculography and electrocardiographic monitoring and 2 laboratory mental stressors (Speech and Stroop) after being withdrawn from cardiac medications. In addition, 48-hour ambulatory electrocardiograms were recorded during routine daily activities. Patients with a history of angina within the past 3 months reported angina during the bicycle or treadmill test with a much higher frequency than patients without such an anginal history (77% vs 26%). Ejection fraction (EF) responses to the Stroop test were abnormal in 48% of patients with an abnormal EF response to the Speech task, versus 17% in patients with a normal EF response (p

Background and Purpose —We sought to determine risk factors for stroke and stroke type in persons with isolated systolic hypertension (ISH). Methods —We performed proportional hazards analyses of data from the Systolic Hypertension in the Elderly Program, a double-blind, randomized, placebo-controlled trial of 4736 persons aged ≥60 years with ISH (systolic blood pressure, 160 to 219 mm Hg; diastolic blood pressure, Results —During an average follow-up of 4.5 years, 384 strokes or TIAs and 262 strokes (including 217 ischemic, 66 lacunar, 26 atherosclerotic, and 25 embolic strokes) were documented. In multivariate analyses, placebo treatment, older age, smoking, history of diabetes, higher systolic blood pressure, lower HDL cholesterol, and ECG abnormality were significantly associated ( P Conclusions —In older persons with ISH, history of diabetes and smoking are important risk factors for lacunar stroke, whereas carotid bruit and age are important risk factors for atherosclerotic and embolic stroke, respectively.

Abstract —Dietary salt restriction is a recommended adjunct with antihypertensive therapy. There may be racial differences in blood pressure response to salt restriction while on antihypertensive therapy. We performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (black, n=96; Hispanic, n=63; white, n=232). Participants were initially preselected for stage I to III hypertension and then further selected for salt sensitivity (≥5 mm Hg increase in diastolic blood pressure after 3 weeks of low salt [≤88 mmol/d Na + ] and high salt [>190 mmol/d Na + ] diet). We compared the antihypertensive effect of an angiotensin-converting enzyme inhibitor (enalapril 5 or 20 mg BID) or a calcium channel antagonist (isradipine 5 or 10 mg BID) during alternating periods of high and low salt intake. The main outcome measure was blood pressure change and absolute blood pressure level achieved with therapy. During the high salt diet (314.7±107.5 mmol/d urinary Na + ) there was greater downward change in blood pressure with both enalapril and isradipine compared with the low salt diet (90.1±50.8 mmol/d Na + ); however, the absolute blood pressure achieved in all races was consistently lower on a low salt diet for both agents. Black, white, and Hispanic isradipine-treated salt-sensitive hypertensives demonstrated a smaller difference between high and low salt diets (black, −3.6/−1.6 mm Hg; white, −6.2/−3.9 mm Hg; Hispanic, −8.1/−5.3 mm Hg) than did enalapril-treated patients (black, −9.0/−5.3 mm Hg; white, −11.8/−7.0 mm Hg; Hispanic, −11.1/−5.6 mm Hg). On the low salt diet, blacks, whites, and Hispanics had similar blood pressure control with enalapril and isradipine. On the high salt diet, blacks had better blood pressure control with isradipine than with enalapril, whereas there was no difference in the blood pressure control in whites and Hispanics treated with either drug. Dietary salt reduction helps reduce blood pressure in salt-sensitive hypertensive blacks, whites, and Hispanics treated with enalapril or isradipine. These data demonstrate that controlling for salt sensitivity diminishes race-related differences in antihypertensive activity.

Background Whether subjects identified as being at increased risk of coronary heart disease (CHD) death by heart rate adjustment of exercise-induced ST-segment depression will benefit from therapy aimed at reducing risk factors has not been examined. Methods and Results Exercise ECGs were performed in 11 880 men from the Usual Care (UC) and Special Intervention (SI) groups of the Multiple Risk Factor Intervention Trial. UC men were referred to customary sources of care in the community; SI men received counseling on smoking cessation and dietary reduction of cholesterol, and stepped-care therapy for hypertension. An abnormal ST-segment response to exercise was defined according to standard criteria as ≥100 μV of additional horizontal or downsloping ST-segment depression and by an ST-segment/heart rate (ST/HR) index >1.60 μV/bpm. After 7 years of follow-up, CHD mortality was significantly lower in SI than UC men with an abnormal ST/HR index (2.4%, 19/786 versus 5.3%, 39/729, P =.005) but was comparable in SI and UC men with a normal ST/HR index (1.6%, 84/5154 versus 1.3%, 70/5211, P =NS). Risk reduction in SI men with an abnormal ST/HR index was independent of age and other cardiac risk factors. In contrast, there was no significant difference in CHD death rate between the smaller groups of SI and UC men with an abnormal test by standard criteria (3.6%, 7/192 versus 2.7%, 5/186, P =NS). Conclusions An abnormal ST/HR index identifies men in whom therapy aimed at reducing CHD risk factors reduces the risk of CHD death by 61%. These findings support the application of heart rate adjustment of ST depression for screening of asymptomatic subjects at increased risk of CHD to identify those who will benefit most from risk factor–reduction programs.

PURPOSE: The Multiple Risk Factor Intervention Trial (MRFIT), a randomized clinical trial for the primary prevention of coronary heart disease, enrolled 12,866 men (including 8194 cigarette smokers) aged 35–57 years at 22 clinical centers across the United States. Participants were randomized either to special intervention (SI), which included an intensive smoking cessation program, or to usual care (UC). After 16 years of follow-up, lung cancer mortality rates were higher in the SI than in the UC group. Since rates of smoking cessation in SI were higher than those for UC for the 6 years of the trial, and since risk of lung cancer mortality is known to decline with smoking cessation, these results were unexpected. The purpose of the present study was to investigate hypotheses that could explain the higher observed lung cancer mortality rates in the SI as compared with the UC group. METHODS: Analytic methods were employed to determine whether SI and UC participants differed either in baseline characteristics or in characteristics that changed during the trial and to determine whether these differences could explain the higher rates of lung cancer mortality among SI as compared to UC participants. Rates of mortality from coronary heart (CHD) were examined to explore the possibility that prevention of CHD death may have contributed to greater mortality due to lung cancer in the SI group. RESULTS: From randomization through December 1990, 135 SI and 117 UC participants died from lung cancer. The relative difference between the SI and U groups adjusted for age and number of cigarettes smoked per day, was 1.17 (95% CI:0.92–1.51). The greatest difference between the SI and UC groups in lung cancer mortality rates occurred among the heaviest smokers at baseline who did not achieve sustained smoking cessation by year 2. In this group the rates of death from CHD were approximately the same among the SI and UC subjects. No differences in baseline characteristics were found between SI and UC smokers who did not achieve sustained cessation by year 2, and there were no differences in follow-up characteristics between the two study groups that could explain the difference in lung cancer mortality. CONCLUSIONS: None of the hypotheses proposed to explain the unexpected higher rates of lung cancer mortality among SI as compared with UC subjects were sustained by the data. Thus we conclude that the difference observed is due to chance, and that a longer period of sustained smoking cessation plus follow-up is necessary to detect a reduction in lung cancer mortality as a result of smoking cessation intervention in a randomized clinical trial.

The workshop discussions focused on how low-density lipoprotein cholesterol (LDL-C) goal attainment can be enhanced with the use of health information technology (HIT) in different clinical settings. A gap is acknowledged in LDL-C goal attainment, but because of the passage of the American Recovery & Reinvestment Act and the Health Information Technology for Economic and Clinical Health Acts there is now reason for optimism that this gap can be narrowed. For HIT to be effectively used to achieve treatment goals, it must be implemented in a setting in which the health care team is fully committed to achieving these goals. Implementation of HIT alone has not resulted in reducing the gap. It is critical to build an effective management strategy into the HIT platform without increasing the overall work/time burden on staff. By enhancing communication between the health care team and the patient, more timely adjustments to treatment plans can be made with greater opportunity for LDL-C goal attainment and improved efficiency in the long run. Patients would be encouraged to take a more active role. Support tools are available. The National Lipid Association has developed a toolkit designed to improve patient compliance and could be modified for use in an HIT system. The importance of a collaborative approach between nongovernmental organizations such as the National Lipid Association, National Quality Forum, HIT partners, and other members of the health care industry offers the best opportunity for long-term success and the real possibility that such efforts could be applied to other chronic conditions, for example, diabetes and hypertension.

The relation between the circadian occurrence of ventricular premature depolarizations (VPD) and sudden arrhythmic death was examined in a subset of patients entered into the Cardiac Arrhythmia Suppression Trial (CAST). Ambulatory electrocardiographic recordings with hourly measurement of VPD frequency were available in 357 patients. Forty percent of the patients (142 of 357) demonstrated circadian variation in VPD frequency between 6:00 a.m. and 9:59 a.m. that was significantly higher (p (Am J Cardiol 1996;78:881–885)

The year 1995 has been an unsettling one in the history of the treatment of hypertension and ischemic heart disease. A fierce debate has sprung up about the safety of calcium antagonists, particularly the dihydropyridine nifedipine. A widely publicized case-control study showed that compared with diuretics and beta-blockers, short-acting calcium antagonists, when used in the treatment of hypertension, were associated with a higher risk of myocardial infarction, an effect which appeared to be dose related. A second study focused on clinical trials of nifedipine in patients primarily with acute myocardial ischemia syndromes. The meta-analysis showed an increased risk in the relative mortality rate of 1.16 associated with the use of short-acting nifedipine at doses of 80 mg/day or higher. The mechanisms responsible for these results were also discussed. Both publications were accompanied by editorials, and there were subsequently other commentaries published which pointed out weaknesses in the design, conduct, analysis and interpretation of the studies, and these have also been reviewed. Arising from this controversy, important questions have been raised which need to be addressed. First, are the data valid and are these drugs safe? If not, can the data be extrapolated from short-acting dihydropyridines, to the newer formulations and other sub-classes of calcium antagonists? Second, do these agents reduce cardiovascular morbidity and mortality? Finally, what are the alternatives to their use and the clinical implications? These studies have raised questions about safety, and there is little evidence to show any actual benefit on the incidence of cardiovascular events. For most patients there are clinically tested and proved therapeutic alternatives, i.e. diuretics and beta-blockers, and therefore the burden of proof must now be on those who primarily recommend the use of calcium antagonists. Recommendations and guidelines for treatment, where the primary goal is to reduce cardiovascular morbidity and mortality must be supported by adequate data.

Objectives.We sought to assess the effect of heart rate adjustment of ST segment depression on risk stratification for the prediction of death from coronary artery disease. Background.Standard analysis of the ST segment response to exercise based on a fixed magnitude of horizontal or downsloping ST segment depression has demonstrated only limited diagnostic sensitivity for the detection of coronary artery disease and has variable test performance in predicting coronary artery disease mortality. Heart rate adjustment of the magnitude of ST segment depression has been proposed as an alternative approach to increase the diagnostic and prognostic accuracy of the exercise electrocardiogram (ECG). Methods.Exercise ECGs were performed in 5,940 men from the Usual Care Group of the Multiple Risk Factor Intervention Trial at entry into the study. An abnormal ST segment response to exercise was defined according to standard criteria as ≥ 100 μV of additional horizontal or downsloping ST segment depression at peak exercise. The ST segment/heart rate index was calculated by dividing the change in ST segment depression from rest to peak exercise by the exercise-induced change in heart rate. An abnormal ST segment/heart rate index was defined as >1.60 μV/beats per min. Results.After a mean follow-up of 7 years there were 109 coronary artery disease deaths. Using a Cox proportional hazards model, a positive exercise ECG by standard criteria was not predictive of coronary mortality (age-adjusted relative risk [RR] 1.5,95% condence interval [CI] 0.6 to 3.6, p = 0.39). In contrast, an abnormal ST segment/heart rate index significantly increased the risk of death from coronary artery disease (age-adjusted RR 4.1, 95% CI 2.7 to 6.0, p < 0.0001). Excess risk of death was confined to the highest quintile of ST segment/heart rate index values, and within this quintile, risk was directly related to the magnitude of test abnormality. After multivariate adjustment for age, diastolic blood pressure, serum cholesterol and cigarettes smoked per day, the ST segment/heart rate index remained a significant independent predictor of coronary death (RR 3.6, 95% CI 2.4 to 5.4, p < 0.001). Conclusions.Simple heart rate adjustment of the magnitude of ST segment depression improves the prediction of death from coronary artery disease in relatively high risk, asymptomatic men. These findings strongly support the use of heart rate-adjusted indexes of ST segment depression to improve the predictive value of the exercise ECG.

Phase I of the Trials of Hypertension Prevention (TOHP) was a randomized, multicenter investigation that included double-blind, placebo-controlled testing of calcium and magnesium supplementation among 698 healthy adults (10.5% blacks and 31% women) aged 30 to 54 years with high-normal diastolic blood pressure (DBP) (80 to 89 mm Hg). Very high compliance (94 to 96% by pill counts) with daily doses of 1 g of calcium (carbonate), 360 mg of magnesium (diglycine), or placebos was corroborated for the active supplements by significant net increases in all urine and serum compliance measures in white men and for urine compliance measures in white women. Overall, neither calcium nor magnesium produced significant changes in blood pressure at 3 and 6 months. Analyses stratified by baseline intakes of calcium, magnesium, sodium, or initial blood pressures also showed no effect of supplementation. These analyses suggested that calcium supplementation may have resulted in a DBP decrease in white women and that response modifiers in this subgroup might have included lower initial urinary calcium levels, urinary sodium levels, or lower body mass index. However, overall analyses indicated that calcium and magnesium supplements are unlikely to lower blood pressure in adults with high-normal DBP. The subgroup analyses, useful to formulate hypotheses, raise the possibility of a benefit to white women, which requires testing in future trials.

We conducted a randomized, double-blind, placebo-controlled trial of oral potassium chloride supplementation (60 mmol/d) in 353 men and women with an initial average diastolic blood pressure between 80 and 89 mm Hg. In the active (n = 178) compared to the placebo (n = 175) treatment group, the urinary potassium level was significantly (p < 0.001) increased by an average of 44.0 and 42.3 mmol/24 h following 3 and 6 months of therapy, respectively. Compared to placebo, active treatment was associated with a small (mean = 1.8 mm Hg) but significant (p = 0.04) reduction in diastolic blood pressure following 3 months of therapy. Following 6 months, however, this apparent treatment effect had virtually disappeared (mean reduction in diastolic blood pressure = 0.3 mm Hg). There was no significant effect of potassium supplementation on systolic blood pressure at either follow-up visit. There was a significant, independent, dose-response relationship between change in both 24-hour urinary potassium excretion and urinary sodium-potassium ratio and the corresponding change in diastolic blood pressure (-1.49 mm Hg for the highest versus the lowest quartile of change in urinary potassium excretion.

Phase II of the Trials of Hypertension Prevention (TOHP) is a multicenter, randomized trial sponsored by the National Heart, Lung, and Blood Institute designed to test whether weight loss alone, sodium reduction alone, or the combination of weight loss and sodium reduction will decrease diastolic (DBP) and systolic blood pressure (SBP) as well as the incidence of hypertension (DBP > or = 90 mm Hg, SBP > or = 140 mm Hg, and/or use of antihypertensive medications) in subjects with high-normal DBP (83 to 89 mm Hg) and SBP less than 140 mm Hg at entry. These interventions were chosen for longer-term testing with end points including hypertension prevention as well as blood pressure (BP) change based on their demonstrated short-term efficacy in reducing BP in phase I of TOHP. The phase II study population is comprised of 2382 participants (1566 men and 816 women) who are 110 to 165% of desirable body weight, allocated at random to the four treatment arms using a 2 x 2 factorial design. The trial has 80% power to detect an overall treatment effect on DBP of 1.2 mm Hg for weight loss or sodium reduction and a difference of 1.6 mm Hg between the combined intervention and placebo groups. BP observers are blinded to participant treatment assignments. Participants will be followed for 3 to 4 years. This trial may have important public policy implications concerning the ability of life-style modifications to reduce BP and prevent the development of hypertension over the long term, thereby avoiding the need for drug therapy which while effective is costly and may have side effects.

Phase II of the Trials of Hypertension Prevention (TOHP II) is a multicenter, controlled clinical trial designed to test whether weight loss, a reduced sodium intake, or a combination of weight loss and a reduced sodium intake will lower blood pressure (BP) and prevent the occurrence of hypertension. The study population consists of middle-aged, moderately overweight individuals with a diastolic BP between 83 and 89 mm Hg. Of the 2382 randomized participants, 816 (34%) are female and 494 (21%) are from a racial or ethnic minority background. At baseline, mean dietary intakes of sodium, based on measurements of 24-hour urinary excretion, were 199 mmol/d in men and 154 mmol/d in women. The average body mass index was 30.9 kg/m2. Across the four randomized groups, there was no substantial imbalance in the distribution of baseline variables; however, the mean age in the four groups was slightly but significantly different (range: 43.2 to 44.2 years, P = 0.02). A comparison of baseline characteristics of TOHP II participants with those of participants in three other primary prevention trials reveals a high level of mean dietary sodium intake in each study. Data reported in this article indicate that any subsequent differences in BP among the randomized groups are unlikely to result from maldistribution of known confounding variables at baseline. Finally, because of the high prevalence of overweight and excessive sodium intake in the United States, results from TOHP II should be broadly applicable to the general population.

Background The M ultiple R isk F actor I ntervention T rial evaluated a multifactor intervention on coronary heart disease ( CHD ) in 12 866 men. A priori defined endpoints ( CHD death, CHD death or nonfatal myocardial infarction, cardiovascular disease [ CVD ] death, and all‐cause death) did not differ significantly between the special intervention ( SI ) and usual care ( UC ) groups over an average follow‐up period of 7 years. Event rates were lower than anticipated, reducing power. Other nonfatal CVD outcomes were prespecified but not considered in composite outcomes comparing SI with UC . Methods and Results Post‐trial CVD mortality risks associated with nonfatal CVD events occurring during the trial were determined with C ox regression. Nonfatal outcomes associated with >2‐fold risk of CVD death over the subsequent 20 years were combined with during‐trial deaths to create 2 new composite outcomes. SI / UC hazard ratios and 95% confidence intervals were estimated for each composite outcome. Of 10 during‐trial nonfatal events, 6 were associated ( P 2‐fold risk of CVD death. A CHD composite outcome ( CHD death, myocardial infarction [clinical or serial ECG change], CHF , or coronary artery surgery) was experienced by 520 SI and 602 UC men ( SI / UC hazard ratio = 0.86; 95% confidence interval, 0.76–0.97; P =0.01). A CVD composite outcome ( CHD [as above], other CVD deaths, stroke, or renal impairment) was experienced by 581 SI and 652 UC men (hazard ratio = 0.89; 95% confidence interval, 0.79–0.99; P =0.04). Conclusions In post hoc analyses, composite fatal/nonfatal CHD and CVD rates over 7 years were significantly lower for SI than for UC . These findings reinforce recommendations for improved dietary/lifestyle practices, with pharmacological therapy as needed, to prevent and control major CVD risk factors.

According to current guidelines from the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), the target low-density lipoprotein cholesterol (LDL-C) level for patients with established coronary heart disease (CHD) or CHD risk equivalents is less than 100 mg/dL, with an optional target of less than 70 mg/dL. More recent data suggest, however, that the physiologically normal level of LDL-C and the level at which atherogenesis is initiated is much lower. Overall, the data convincingly demonstrate that LDL-C lowering is associated with a significant reduction in CHD events, regardless of preexisting CHD. The NCEP ATP III treatment guidelines, published in 2002 and updated in 2004, do not reflect more recent findings on intensive lipid-lowering therapy, which are likely be addressed in the NCEP ATP IV guidelines, scheduled to be released in 2011. Drug options for LDL-C lowering include statins (the drug of choice), bile acid sequestrants, nicotinic acid, fibrates, and selective cholesterol absorption inhibitors.

Although medical students are increasingly taught about the nature and importance of cardiovascular risk factors, they are less often taught how to talk about them with patients and how to encourage patients to modify certain behaviors (e.g., smoking), which are associated with high risk for cardiovascular disease. The authors describe a short educational module designed to help third year psychiatry clerks learn some practical, patient-oriented aspects of preventive cardiology. From a small group discussion that encourages active participation, students learn to assess and explore environmental factors, skill deficits, cognitive distortions and emotions that may prevent patients from changing high-risk behavior. Strategies for change are then suggested, discussed and assessed for effectiveness in sample situations. This type of module is readily adoptable into most medical school psychiatry curricula and, if widely used, could promote the necessary skills to effectively change high-risk behaviors and lead to a further reduction in cardiovascular disease.

The Multiple Risk Factor Intervention Trial (MRFIT) was designed as a primary prevention study to test the effect of multifactorial intervention on long-term outcome in men with a combination of risk factors that placed them in the top 10-15 percentiles of risk for coronary artery disease. Of the 12,866 patients in this study, the 3,600 men (about 28%) with abnormalities in the baseline electrocardiogram were prospectively identified. They were expected to be at increased risk for coronary events compared with those without electrocardiographic abnormalities. Analysis of cumulative mortality data following antihypertensive regimens that included high dosages of diuretics revealed an association between electrocardiographic abnormalities at rest and diuretic treatment that related to adverse outcome. When the dosages of the diuretic were lowered, this trend was reversed. It is proposed that diuretic-related hypokalemia may predispose patients who may have silent myocardial ischemia to potentially fatal arrhythmias and that use of potassium-sparing antihypertensive regimens be considered in high-risk hypertensive patients.

Hypertension (HTN) continues to be a serious public health problem in the United States and is a major risk factor for stroke, heart failure, myocardial infarction, and other serious cardiovascular and renal diseases. Because HTN can be asymptomatic, its detection and control continues to be a challenge. The total economic burden of HTN is estimated at $73.4 billion in 2009.To examine the potential prognostic utility of biomarkers to assess hypertension-related cardiovascular risk and their potential impact on treatment in the context of current epidemiology and demographics of HTN.Although blood pressure control rates among people treated for HTN have increased from 51.3 percent to 63.9 percent over the past five years, there remains a vast unmet need for improved efficiency and effectiveness in diagnosis and treatment. Biomarkers provide a promising approach to improve detection and management of disease progression while optimizing health care expenditures.

Activation of the sympathetic nervous system plays an important role in the development and maintenance of essential hypertension and the subsequent development of cardiac hypertrophy, heart failure, and sudden cardiac death. Current research suggests that pharmacologic treatment of hypertension should be aimed not only at lowering blood pressure, but also at inhibiting sympathetic drive.

Beta-blockers are an established class in the management of hypertension, and numerous randomized, controlled trials have shown that these drugs can prevent cardiovascular events in this population. However, beta-blockers are underutilized in managing the general hypertensive population. This phenomenon may stem in part from concerns about side effects. On the contrary, beta-blockers demonstrate comparable efficacy, safety, and tolerability compared with other classes of antihypertensive drugs. Because beta-blockers offer unique cardiovascular protection, they should be considered an integral part of the treatment regimen for patients with hypertension who are at risk for cardiovascular events.

This open, multicenter phase III study was designed to assess the efficacy and long-term safety of terazosin (1 to 40 mg/day), alone or in combination with other antihypertensive drugs, in 364 patients with mild to moderate essential hypertension. Compared with baseline values, long-term terazosin monotherapy or combination therapy resulted in consistent decreases in both systolic and diastolic blood pressures, with a mean reduction in supine diastolic pressure of 12 to 14 mm Hg. The numbers of patients with controlled blood pressure at the last evaluable visit of each therapy period were as follows: terazosin alone, 106 of 245 (43%); terazosin with added diuretic, 70 of 112 (63%); diuretic with added terazosin, 47 of 88 (53%); and terazosin plus diuretic with added β-blocker, 22 of 32 (69%). Most adverse events were mild or moderate in severity. Only pain in extremities had a higher incidence during long-term treatment (6%, 181 to 360-day period) than during initial short-term treatment (5%, 1 to 90-day period). Three of six syncopal events occurred during the initial 180 days of treatment; this 0.8% ( 3 364 ) incidence was comparable with that reported previously for short-term studies. Only one case of syncope occurred during terazosin monotherapy. Terazosin was judged to be a safe and effective long-term medication for the treatment of hypertension.

Background In patients with prior myocardial infarction (MI), β-blockers reduce mortality by 23% to 40%. However, despite this favorable effect, adverse effects limit compliance to this medication. The purpose of the study was to compare a β-blocker–based strategy with a heart rate–lowering calcium antagonists–based strategy in patients with prior MI. Methods We evaluated 7,218 patients with prior MI enrolled in the INternational VErapamil SR-Trandolapril (INVEST) substudy randomized to verapamil-sustained release (SR)– or atenolol-based strategies. Primary outcome was time to first occurrence of death (all-cause), nonfatal MI, or nonfatal stroke. Secondary outcomes included death, total MI (fatal and nonfatal), and total stroke (fatal and nonfatal) considered separately. Results During the 2.8 ± 1.0 years of follow-up, patients assigned to the verapamil-SR–based and atenolol-based strategies had comparable blood pressure control, and the incidence of the primary outcome was equivalent. There was no difference between the 2 strategies for the outcomes of either death or total MI. However, more patients reported excellent/good well-being (82.3% vs 78.0%, P = .02) at 24 months with a trend toward less incidence of angina pectoris (12.0% vs 14.3%, adjusted P = .07), nonfatal stroke (1.4% vs 2.0%; P = .06), and total stroke (2.0% vs 2.5%, P = .18) in the verapamil-SR–based strategy group. Conclusions In hypertensive patients with prior MI, a verapamil-SR–based strategy was equivalent to a β-blocker–based strategy for blood pressure control and prevention of cardiovascular events, with greater subjective feeling of well-being and a trend toward lower incidence of angina pectoris and stroke in the verapamil-SR–based group.