Achieving blood pressure goals globally: five core actions for health-care professionals. A worldwide call to action.

The prevalence of hypertension continues to rise across the world, and most patients who receive medical intervention are not adequately treated to goal. A Working Group including representatives of nine international health-care organizations was convened to review the barriers to more effective blood pressure control and propose actions to address them. The group concluded that tackling the global challenge of hypertension will require partnerships among multiple constituencies, including patients, health-care professionals, industry, media, health-care educators, health planners and governments. Additionally, health-care professionals will need to act locally with renewed impetus to improve blood pressure goal rates. The Working Group identified five core actions, which should be rigorously implemented by practitioners and targeted by health systems throughout the world: (1) detect and prevent high blood pressure; (2) assess total cardiovascular risk; (3) form an active partnership with the patient; (4) treat hypertension to goal and (5) create a supportive environment. These actions should be pursued with vigour in accordance with current clinical guidelines, with the details of implementation adapted to the economic and cultural setting.

Effect of mibefradil, a T-type calcium channel blocker, on morbidity and mortality in moderate to severe congestive heart failure: the MACH-1 study. Mortality Assessment in Congestive Heart Failure Trial.

BACKGROUND: Calcium antagonists have proved disappointing in long-term congestive heart failure (CHF) studies. Mibefradil, a new calcium antagonist that selectively blocks T-type calcium channels, has been shown to be an effective antihypertensive, antianginal, and anti-ischemic agent, and because of its different mechanism of action, it may be beneficial as adjunct therapy in CHF patients. METHODS AND RESULTS: This multicenter, randomized, double-blind study compared mibefradil with placebo as adjunct to usual therapy in 2590 CHF patients (NYHA class II to IV; left ventricular fraction <35%). The initial 50-mg daily dose of mibefradil was uptitrated to 100 mg after 1 month and continued up to 3 years. Patients were monitored at 1 week; 1, 2, and 3 months; and every 3 months thereafter. All-cause mortality, cardiovascular mortality, and cardiovascular morbidity/mortality were analyzed by use of the log-rank test (alpha=0.05). Substudies included exercise tolerance, plasma hormone and cytokines, echocardiography, and quality of life. Total mortality was similar between mibefradil- and placebo-treated patients (P=0.151). The 14% increased risk of mortality with mibefradil in the first 3 months was not statistically significant (P=0.093). Treatment groups had similar cardiovascular mortality (P=0.246), cardiovascular morbidity/mortality (P=0.783), and reasons for death or hospitalization. Patients comedicated with mibefradil and antiarrhythmics (class I or III), including amiodarone, had a significantly increased risk of death. Substudies demonstrated no significant differences between treatments. CONCLUSIONS: When used as adjunct therapy, mibefradil did not affect the usual outcome of CHF. The potential interaction with antiarrhythmic drugs, especially amiodarone, and drugs associated with torsade de pointes may have contributed to poor outcomes early in the study.

Patent foramen ovale: a review of associated conditions and the impact of physiological size.

Patent foramen ovale (PFO) is implicated in platypnea-orthodeoxia, stroke and decompression sickness (DCS) in divers and astronauts. However, PFO size in relation to clinical illness is largely unknown since few studies evaluate PFO, either functionally or anatomically. The autopsy incidence of PFO is approximately 27% and 6% for a large defect (0.6 cm to 1.0 cm). A PFO is often associated with atrial septal aneurysm and Chiari network, although these anatomic variations are uncommon. Methodologies for diagnosis and anatomic and functional sizing of a PFO include transthoracic echocardiography (TTE), transesophageal echocardiography (TEE) and transcranial Doppler (TCD), with saline contrast. Saline injection via the right femoral vein appears to have a higher diagnostic yield for PFO than via the right antecubital vein. Saline contrast with TTE using native tissue harmonics or transmitral pulsed wave Doppler have quantitated PFO functional size, while TEE is presently the reference standard. The platypnea-orthodeoxia syndrome is associated with a large resting PFO shunt. Transthoracic echocardiography, TEE and TCD have been used in an attempt to quantitate PFO in patients with cryptogenic stroke. The larger PFOs (approximately > or =4 mm size) or those with significant resting shunts appear to be clinically significant. Approximately two-thirds of divers with unexplained DCS have a PFO that may be responsible and may be related to PFO size. Limited data are available on the incidence of PFO in high altitude aviators with DCS, but there appears to be a relationship. A large decompression stress is associated with extra vehicular activity (EVA) from spacecraft. After four cases of serious DCS in EVA simulations, a resting PFO was detected by contrast TTE in three cases. Patent foramen ovales vary in both anatomical and functional size, and the clinical impact of a particular PFO in various situations (platypnea-orthodeoxia, thromboembolism, DCS in underwater divers, DCS in high-altitude aviators and astronauts) may be different.

Short- and long-acting angiotensin-converting enzyme inhibitors: a randomized trial of lisinopril versus captopril in the treatment of congestive heart failure. The Multicenter Lisinopril-Captopril Congestive Heart Failure Study Group.

A randomized, parallel, double-blind study was performed with lisinopril, a long-acting angiotensin-converting enzyme inhibitor, versus captopril, a shorter-acting angiotensin-converting enzyme inhibitor, in the treatment of congestive heart failure. All patients were in New York Heart Association class II, III or IV and had remained symptomatic despite therapy with digoxin and diuretics. After a 4 to 14 day placebo baseline period, patients were randomized to receive either lisinopril, 5 mg orally once per day (n = 94), or captopril, 12.5 mg orally three times per day (n = 95), in addition to continuation of digoxin and diuretics. The dose of study drug could be doubled at 4 week intervals for a total of 12 weeks of double-blind therapy. The maximal dose was 20 mg once per day of lisinopril or 50 mg three times per day of captopril. The addition of either lisinopril or captopril to a regimen of diuretics or digoxin, or both, caused an increase in exercise duration as assessed on a motorized treadmill. When protocol violators were excluded, patients receiving lisinopril had a statistically greater increase in exercise duration than that of patients receiving captopril. In patients with renal impairment (serum creatinine greater than 1.6 mg/dl at baseline), lisinopril was superior to captopril in improving exercise duration. Lisinopril, but not captopril, increased left ventricular ejection fraction in patients with moderately to severely (less than 35%) decreased function (p less than 0.05). Improvement in functional capacity and quality of life, as assessed by the Yale Scale dyspnea/fatigue index, was significantly greater for the lisinopril group.(ABSTRACT TRUNCATED AT 250 WORDS)

Randomized placebo-controlled trial of amlodipine in vasospastic angina. Amlodipine Study 160 Group.

OBJECTIVES: This study was designed to assess the efficacy and safety of amlodipine, a long-acting calcium channel blocker, in patients with vasospastic angina. BACKGROUND: Previous studies have established the value of short-acting calcium channel blockers in the treatment of coronary spasm. METHODS: Fifty-two patients with well documented vasospastic angina were entered into the present study. After a single-blind placebo run-in period, patients were randomized (in a double-blind protocol) to receive either amlodipine (10 mg) or placebo every morning for 4 weeks. Twenty-four patients received amlodipine and 28 received placebo. All patients were given diaries in which to record both the frequency, severity, duration and circumstances of anginal episodes and their intake of sublingual nitroglycerin tablets. RESULTS: The rate of anginal episodes decreased significantly (p = 0.009) with amlodipine treatment compared with placebo and the intake of nitroglycerin tablets showed a similar trend. Peripheral edema was the only adverse event seen more frequently in amlodipine-treated patients. No patient was withdrawn from the double-blind phase of the study because of an adverse event. Patients who completed the double-blind phase as responders to amlodipine or as nonresponders to placebo were offered the option of receiving amlodipine in a long-term, open label extension phase. During the extension, the daily dose of amlodipine was adjusted to 5 or 15 mg if needed and the rate of both anginal episodes and nitroglycerin tablet consumption showed statistically significant decreases between baseline and final assessment. CONCLUSION: This study suggests that amlodipine given once daily is efficacious and safe in the treatment of vasospastic angina.

Remodeling and reparation of the cardiovascular system.

Growth or altered metabolism of nonmyocyte cells (cardiac fibroblasts, vascular smooth muscle and endothelial cells) alters myocardial and vascular structure (remodeling) and function. However, the precise roles of circulating and locally generated factors such as angiotensin II, aldosterone and endothelin that regulate growth and metabolism of nonmyocyte cells have yet to be fully elucidated. Trials of pharmacologic therapy aimed at preventing structural remodeling and repairing altered myocardial structure to or toward normal in the setting of hypertension, heart failure and diabetes are reviewed. It is proposed that these are therapeutic goals that may reduce cardiovascular morbidity and mortality. Although this hypothesis remains unproved the primary goal of therapy should be to preserve or restore tissue structure and function.

Coronary artery pain. A possible cause of graft occlusion in a patient with fixed obstructive coronary artery disease.

We describe a 50-year-old man with rest angina and ECG anterior wall subendocardial ischemia. During coronary angiography, a high-grade proximal left anterior descending stenosis was present. Spontaneous total spasm distal to the lesion occurred without chest pain or ST segment shifts. The patient underwent aortocoronary bypass surgery and continued to have the same pain as preoperatively. Repeated catheterization demonstrated total occlusion of the bypass graft with unchanged native coronary vessels. This suggests prolonged coronary artery spasm as the mechanism for graft occlusion.

Remission of mild to moderate hypertension after treatment with carteolol, a beta-adrenoceptor blocker with intrinsic sympathomimetic activity.

Previous studies have indicated that some hypertensive patients, following a period of effective treatment with certain antihypertensive drugs, may experience prolonged normotension after drug withdrawal. We have studied the ability of carteolol, a nonselective beta-adrenoceptor antagonist with intrinsic sympathomimetic activity, to produce such remissions of hypertension. Thirty-four patients whose diastolic blood pressure was controlled at 90 mm Hg or less with carteolol monotherapy (2.5 to 5.0 mg/d for an average of 328 days) were randomized to a nine-month, double-blind, placebo-controlled drug-withdrawal trial. Those patients randomized to continue carteolol therapy had initially responded to carteolol treatment with reduction in blood pressure from 151 +/- 4/99 +/- 2 to 132 +/- 4/80 +/- 2 mm Hg. Those randomized to treatment with placebo had initially responded with blood pressure reductions from 154 +/- 4/97 +/- 2 to 137 +/- 4/81 +/- 2 mm Hg. Changes in mean systolic and diastolic blood pressure (mm Hg +/- SEM) from baseline during carteolol therapy to the final visit at nine months were not different for patients receiving placebo (13 +/- 5/6 +/- 4 mm Hg, recumbent; 11 +/- 6/4 mm Hg, standing) or carteolol (11 +/- 5/7 +/- 3 mm Hg, recumbent; 12 +/- 6/7 +/- 3 mm Hg, standing). The final mean recumbent diastolic blood pressure (86.9 mm Hg) was the same in both groups. Prolonged normotension may follow a period of carteolol treatment, again suggesting the potential importance of periodic withdrawal of antihypertensive medication.

Treatment of isolated systolic hypertension with labetalol in the elderly.

Antihypertensive therapy with labetalol was evaluated in a prospective, randomized, multicenter, double-blind study of 133 elderly patients with isolated systolic hypertension (standing systolic blood pressure [BP] greater than or equal to 160 mm Hg; diastolic BP less than 95 mm Hg). Following a placebo-washout period, patients received either labetalol (n = 70) or placebo (n = 63), which was titrated as necessary from 100 to 400 mg twice a day over a 6-week period. Once the BP was controlled (standing systolic BP less than 160 mm Hg, and greater than or equal to 10-mm Hg decrease from baseline) or the maximum dosage had been given, patients continued receiving the same regimen until the end of the titration period and throughout a 4-week maintenance period. Blood pressure was controlled in 57 (81%) of 70 of the labetalol-treated patients (86% receiving less than or equal to 200 mg twice a day) compared with 34 (54%) of 63 of the placebo-treated patients. Throughout the active treatment periods, BP was significantly lower in patients treated with labetalol compared with those taking placebo; mean standing systolic BP decreased 26 mm Hg in the labetalol group vs 9 mm Hg in the placebo group. Side effects were generally mild, and the dropout rates due to adverse experiences were similar between treatment groups (14% in the labetalol group vs 10% in the placebo group). In summary, labetalol can effectively lower systolic BP in the elderly without causing adverse orthostatic changes.

Antihypertensive therapy and cardiovascular risk. Are all antihypertensives equal?

The lack of success of antihypertensive drug therapy in decreasing cardiovascular events has caused close examination of the influence of antihypertensive drugs on cardiac risk factors. Striking differences exist in the pharmacological profiles of antihypertensive drug classes and subclasses as well as in the influences of the drugs on electrolyte, lipid, and glucose metabolism. Differences also exist in the effects of the drugs on left ventricular hypertrophy. These differences in the effects of antihypertensive drugs on cardiac risk factors may assist in explaining the lack of a favorable effect on cardiovascular events in previous clinical trials. However, prospective trials are necessary to demonstrate that treatment of hypertension with drugs that have a more favorable effect on cardiac risk factors will reduce cardiac events (i.e., myocardial infarction, heart failure, and sudden death).

Immunoreactive plasma concentrations of an endogenous antiopiate are higher in spontaneously hypertensive rats than in Wistar-Kyoto rats.

Tyrosine-MIF-1 (Tyr-Pro-Leu-Gly-NH2) is present in rat brain in varying concentrations throughout the day and can act as an opiate antagonist. Since altered sensitivity to pain is known to occur in hypertension, plasma and brain concentrations of Tyr-MIF-1--like immunoreactivity were measured in spontaneously hypertensive rats (SHR) and compared every 4 hours for 24 hours with the concentrations in control Wistar-Kyoto rats (WKY). The Tyr-MIF-1--like immunoreactivity in plasma was significantly higher in SHR than in the WKY at each interval; the mean difference was 62% (p less than 0.001). High-performance liquid chromatography demonstrated that peak immunoreactivity eluted in the same position as the synthetic tetrapeptide. Brain concentrations of the peptide were not reliably different between SHR and WKY. The diurnal rhythm was particularly evident in SHR: the highest concentrations of peptide in both brain and plasma occurred at 2000 hours. These results suggest the presence of another difference between SHR and WKY.

Effect of glucagon on digital circulation.

The effect of glucagon on the digital circulation was studied in 7 subjects using the digital rheoplethysmograph (RPG). Rheoplethysmograms were continuously recorded while glucagon (0.1 to 2.0 mg) was injected into the brachial artery of the same extremity being studied with the RPG. The injection of glucagon was associated with a "tingling" or "burning" sensation in 3 subjects. The initial response, which was maximal 8 to 27 sec after the injection of glucagon, was constriction of the arteries, veins, and A-V shunts. The late response consisted of reopening of the arteries and veins. However, in some patients, there was RPG evidence of persistent constriction of the A-V shunts. It is suggested that the late response is similar to that observed in reactive hyperemia and following injection of bradykinin and, therefore, may be related to local release of vasoactive substances by glucagon.

Time-dependent antihypertensive effect of carteolol--a beta-adrenoceptor antagonist with partial agonist activity.

The antihypertensive effect of carteolol (0.5 to 60 mg daily), a beta-adrenoceptor antagonist with partial agonist activity, was studied in a double-blind parallel protocol. A 3-wk placebo period was followed by an 8-wk treatment period during which patients received 0.5, 2.5, 20, and 60 mg in an increasing (group 1) or decreasing (group 2) manner for successive 2-wk intervals, followed by a 2- to 6-wk withdrawal period. Resting supine and standing blood pressures (BP) and heart rates (HR) were measured at each visit. Isometric handgrip exercise and treadmill exercise were used to evaluate beta-blockade. Plasma carteolol concentration was measured by radioimmunoassay. Recumbent BP fell from 154 +/- 10/100 +/- 2 to 143 +/- 10/84 +/- 11 mm Hg for group 1 and from 153 +/- 10/100 +/- 3 to 138 +/- 14/78 +/- 8 mm Hg for group 2 after 8 wk of treatment. HR was unchanged. The greater reduction in BP for each dose was observed with the later administrations, but was not related to serum concentration. beta-Blockade was evident at all doses of carteolol. Carteolol is an effective antihypertensive. Duration of carteolol therapy, independent of dosage, is important in its effectiveness.

Short-term effects of intravenous clonidine in congestive heart failure.

After intravenous bolus injections of clonidine HCl (150 micrograms) to 12 patients with congestive heart failure, peak effects appeared in 5 to 20 min. Clonidine reduced heart rate from 94 +/- 14 to 82 +/- 14 bpm (mean +/- SD, P less than 0.05), left ventricular filling pressure from 31 +/- 5 to 23 +/- 5 mm Hg (P less than 0.001), mean systemic arterial pressure from 98 +/- 13 to 82 +/- 13 mm Hg (P less than 0.001), mean pulmonary artery pressure from 46 +/- 6 to 38 +/- 6 mm Hg (P less than 0.001), and right atrial pressure from 14 +/- 5 to 11 +/- 5 mm Hg (P less than 0.05). Cardiac index increased from 1.6 +/- 0.4 to 1.8 +/- 0.6 l/min/m2 (P less than 0.05) and stroke volume from 32 +/- 10 to 43+/- 12 ml/beat (P less than 0.05). Systemic vascular resistance decreased from 2,342 +/- 800 to 1,795 +/- 345 dynes sec cm-5 (P less than 0.05) and pulmonary vascular resistance from 365 +/- 158 to 263 +/- 114 dynes sec cm-5 (P less than 0.05). We conclude that clonidine decreases heart rate and left ventricular preload and afterload in congestive heart failure.

Prolonged hemodynamic benefits from a high-dose bolus injection of human atrial natriuretic factor in congestive heart failure.

The physiologic and potential pharmacologic roles of atrial natriuretic factor in congestive heart failure have remained confusing. We have evaluated the hemodynamic responses to human atrial natriuretic factor [ANF (102-126)] given as bolus intravenous doses of 2.0 or 4.5 micrograms/kg to 12 patients with congestive heart failure. Responses were monitored with pulmonary and systemic arterial catheters in place. By 30 minutes after 4.5 micrograms/kg ANF (n = 6), heart rate decreased from 97 +/- 16 to 91 +/- 15 beats/min, right atrial pressure from 14 +/- 4 to 12 +/- 3 mm Hg, and pulmonary capillary wedge pressure from 33 +/- 3 to 23 +/- 2 mm Hg (all p less than 0.05); responses persisted for 120 minutes. Mean arterial pressure, cardiac index, stroke volume index, and pulmonic and systemic vascular resistances did not change significantly. The 2.0 micrograms/kg ANF dose produced similar responses, but only heart rate and right atrial pressure decreased significantly. No clinically important side effects were noted. High-dose ANF bolus doses can be administered simply and safely and improve hemodynamic parameters in chronic heart failure. Therefore ANF does have pharmacologic activity in heart failure and may have therapeutic potential.

Myocardial disease in hypertensive-diabetic patients.

Experimental and clinical evidence points to the existence of a cardiomyopathy associated with diabetes mellitus that is not due to coronary atherosclerosis. The condition is characterized by distinct clinical presentations and physiologic and biochemical abnormalities. Potential mechanisms for the development of diabetic cardiomyopathy are complex but are probably associated, in part, with hyperglycemia and hyperlipidemia. Primary hypertension is also associated with the development of myocardial abnormalities. Many of these changes are similar to those seen in diabetic cardiomyopathy. It is now clear that the co-existence of hypertension and diabetes mellitus produces a more severe cardiomyopathy than that produced by hypertension or diabetes alone. Potential mechanisms for interaction are numerous. Treatment of hypertension in diabetic patients must be targeted to more specific needs. Antihypertensive drugs should not worsen cardiac risk factors or glucose control and should have favorable effects on left ventricular function. The calcium antagonists and angiotensin-converting enzyme inhibitors have pharmacologic profiles that make them attractive as monotherapy for diabetic patients.

Lisinopril and captopril in the treatment of heart failure in older patients. Comparison of a long- and short-acting angiotensin-converting enzyme inhibitor.

Heart failure is a common cardiovascular disorder that increases in prevalence with age. Older patients may respond differently than younger patients to the various classes of drugs used in the treatment of congestive heart failure (CHF). The responses of older patients (at least 65 years of age) were evaluated as part of a large multicenter trial utilizing angiotensin-converting enzyme (ACE) inhibitors in the treatment of CHF. A prospectively planned subgroup analysis of older CHF patients' therapeutic response to the long-acting (approximately 24-hour) ACE inhibitor lisinopril was compared with their response to captopril, a short-acting (less than eight-hour) ACE inhibitor. Symptomatic improvement occurred in both the lisinopril and captopril groups. Exercise duration also improved for patients treated with both agents. However, there was a tendency for lisinopril to be more effective than captopril (p = 0.08). Thus, the low level of renin activity often found in the plasma of older patients did not decrease the ability of the ACE inhibitors to improve effort tolerance. Left ventricular ejection fraction increased in patients treated with lisinopril but not in those treated with captopril. The improvement in left ventricular ejection fraction with lisinopril may be indicative of a more favorable prognosis in patients with CHF, since another long-acting ACE inhibitor, enalapril, reduces the rate of mortality associated with CHF. ACE inhibitors were generally well-tolerated by the older patients in the study. Therefore, ACE inhibitors appear to offer a useful therapeutic approach to the management of CHF in the older age group.

Multiclinic controlled trial of diltiazem for Prinzmetal's angina.

To assess the efficacy of a new calcium entry blocker, diltiazem (Cardizem), for prophylaxis of Prinzmetal's angina, 48 patients were studied in randomized, multiple crossover multiclinic study (2 weeks single-blind, 8 weeks double-blind). Diltiazem dosage in one crossover phase was 120 mg per day; in the other, 240 mg per day. Therapeutic response was measured by patients' diary records of angina frequency and nitroglycerin tablet consumption. Treatment with 120 mg of diltiazem per day reduced angina by 41 percent from the entry placebo period and 20 percent from the paired placebo period (p less than 0.005). Treatment with 240 mg of diltiazem per day reduced angina frequency by 68 percent from the entry placebo period and 43 percent from the paired placebo period (p less than 0.01). There were similar reductions in nitroglycerin consumption. Adverse experiences that may have been related to the medication were noted in only 5 percent of patients. There were no alterations in blood pressure or heart rate. The PR interval increased 3 percent at the 240 mg dosage level. We conclude that diltiazem is an effective and safe agent for control of symptoms of Prinzmetal's angina.

Pharmacoeconomic issues in antihypertensive therapy.

Today's healthcare environment is one of perpetual change, increasing costs, and scarce resources. Healthcare professionals, insurers, and consumers are constantly challenged with balancing healthcare costs and quality of life. With so many antihypertensive agents to choose from, therapies that provide benefits beyond the decreasing of blood pressure, will become the preferred therapies. However, these agents must also demonstrate a desirable side-effect profile; agents that are effective but not complied with will neither reduce costs nor improve quality of life. Angiotensin II receptor antagonists have the most favorable adverse event profile of the antihypertensive agents. These drugs may become the preferred agents of physicians who factor indirect costs--less morbidity and greater productivity--into their selection of an antihypertensive therapy.

Importance of long-acting angiotensin-converting enzyme inhibitors for congestive heart failure.

The renin-angiotensin system (RAS) has both localized and systemic effects in the pathophysiology of heart failure. These may lead to structural changes in the heart and blood vessels as well as to more disseminated symptomatology, including vasoconstriction and both salt and water retention. In association with other neurohormonal mechanisms, such as the sympathetic nervous system, these latter effects result in an elevated work load for the heart. The increase in neurohormonal activity, seen in some patients with heart failure, may result in a loss of circadian variation in heart rate and blood pressure and deprive the heart of a needed reduction in work load during the night. The suppression of such neurohormonal activity through the use of long-acting angiotensin-converting enzyme (ACE) inhibitors, such as lisinopril, provides a means of controlling such symptoms. In comparison with short-acting ACE inhibitors, such long-acting suppression of the RAS may have a number of advantages. These include a more sustained increase in exercise duration, improvement in left ventricular ejection fraction, and, speculatively, a better influence on patient mortality.