The role of alpha 1-blockers in combination therapy for hypertension.

Antihypertensive monotherapy provides adequate blood pressure control in less than 50% of patients with hypertension (BP > 140/90 mmHg), especially those with stage 2-3 disease. This article reviews clinical studies that demonstrate that add-on therapy with an alpha1-blocker (doxazosin, terazosin or prazosin) is an effective and well-tolerated regimen for improving blood pressure control in patients with inadequately controlled hypertension. Furthermore, alpha1-blockers have therapeutic benefits that go beyond blood pressure management. They have a small but positive effect on the serum lipid profile and they have favourable or benign effects on conditions that frequently coexist with hypertension, such as type 2 diabetes mellitus and benign prostatic hyperplasia.

Effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication. Sildenafil Study Group.

OBJECTIVES: To assess the acute effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication. DESIGN: Post-hoc subanalysis of five, 12- or 24-week, prospective, randomized, double-blind, placebo-controlled studies. SETTING: Private-practice and academic urology clinics. PATIENTS: A total of 1685 men with erectile dysfunction of > or = 6 months duration, of whom 667 (sildenafil n = 406, placebo n = 261) were taking antihypertensive medication (diuretic, beta-blocker, alpha-blocker, angiotensin converting enzyme inhibitor, and/or calcium antagonist). Of the patients taking antihypertensive medication, 608 (91%) completed the studies (374 of 406 receiving sildenafil, 234 of 261 receiving placebo). INTERVENTIONS: The last dose of oral sildenafil (25-200 mg) or placebo was taken at home on the morning of the final clinic visit. Patients taking antihypertensive medication maintained usual dosing schedules. MAIN OUTCOME MEASUREMENTS: Sitting systolic (SBP)/diastolic blood pressure (DBP) and heart rate at baseline and after dosing with sildenafil or placebo (end-of-treatment visit). RESULTS: Mean changes from baseline in SBP/DBP for men taking antihypertensive medication were -3.6/-1.9 mmHg for those receiving sildenafil and -0.8/-0.1 mmHg for those receiving placebo compared with -2.2/-2.0 mmHg and -0.1/0.4 mmHg, respectively, for men not taking antihypertensive medication. Mean changes from baseline in heart rate for men taking antihypertensive medication were -0.6 beats/min after sildenafil and 0.9 beats/min after placebo compared with 0.4 beats/min and -0.6 beats/min, respectively, for patients not taking antihypertensive medication. Differences in SBP, DBP, and heart rate between the patients taking and those not taking antihypertensive medication were small. CONCLUSIONS: The acute, short-term effects of oral sildenafil on blood pressure and heart rate in men with erectile dysfunction were small and not likely to be clinically significant in those taking concomitant antihypertensive medication.

Cardiovascular effects of sildenafil citrate and recommendations for its use.

Sildenafil citrate is the first orally active therapy proved to be effective and safe treatment for erectile dysfunction (ED). Because men with cardiovascular disease are at increased risk of developing ED, and because ED and cardiovascular disease share important risk factors, attention has focused recently on the use of sildenafil in these men. When used in combination with nitroglycerin and other nitric oxide (NO) donors, sildenafil may potentiate major drops in blood pressure. Use of nitrate antianginal agents are an absolute contraindication to sildenafil use. In normotensive men and in men receiving antihypertensive medications evaluated in Phase II/III clinical trials, sildenafil use at the recommended doses (25-100 mg 1 hour before sexual intercourse and no more than once daily) was associated with modest, transient reductions in blood pressure and negligible effects on heart rate. In a more recent study, sildenafil was well tolerated in patients receiving antihypertensive medications and was not associated with major decreases in blood pressure. From the time of its approval in the United States in March 1998 through mid-November 1998, with approximately 6 million prescriptions written, 130 deaths were reported by the US Food and Drug Administration (FDA). Seventy-seven of the men who died had documented cardiovascular events. Sixteen men took or were administered nitroglycerin or an organic nitrate; 3 others had nitroglycerin in their possession. Physician prescribing guidelines issued by the American College of Cardiology/American Heart Association (ACC/AHA) recommend caution when prescribing sildenafil to men with certain cardiovascular conditions, liver or kidney disease, and to those taking medications that may prolong sildenafil's half-life (e.g., erythromycin or cimetidine). Those with known or suspected coronary artery disease may benefit from an exercise test to determine whether resumption of sexual activity with use of sildenafil is likely to be associated with an increased risk of myocardial ischemia.

Antiplatelet therapy in the prevention of ischemic vascular events: literature review and evidence-based guidelines for drug selection.

BACKGROUND: New antiplatelet drugs are being developed and many clinical trials evaluating the benefits of antiplatelet drugs for the secondary prevention of ischemic events in patients with atherosclerotic vascular disease have been performed. HYPOTHESIS: An updated systematic review and evidence-based guidelines for the appropriate selection of antiplatelet drugs may be beneficial to physicians and healthcare organizations attempting to create or update current clinical practice guidelines or clinical pathways aimed at caring for these patients. METHODS: (1) A systematic review of the recent literature on the relative efficacy and safety of aspirin, ticlopidine, and clopidogrel was undertaken; (2) an evidence-based, expert panel approach using a modified Delphi technique to create explicit guidelines for prescribing antiplatelet therapy was instituted; and (3) the recommendations of an expert panel were summarized. RESULTS: Consensus guidelines were developed for the utilization of aspirin, ticlopidine, or clopidogrel for the prevention of ischemic events in patients with manifestations of atherosclerotic vascular disease (prior myocardial infarction, prior ischemic stroke, or established peripheral arterial disease) who are at increased risk for recurrent ischemic events. Based on efficacy and safety, clopidogrel was recommended as the drug of choice for patients with established peripheral arterial disease; aspirin or clopidogrel should be considered in patients with prior myocardial infarction (with clopidogrel favored for patients who have had a recurrent event while on aspirin or in whom aspirin is contraindicated); aspirin or clopidogrel should be considered as first-line treatment in patients with prior ischemic (nonhemorrhagic) stroke--however, clopidogrel is the favored drug in patients in whom other antiplatelet drugs are either contraindicated or who have had recurrent events while on therapy. CONCLUSIONS: Myocardial infarction, ischemic stroke, and peripheral arterial disease are all clinical manifestations of the same underlying disease process (atherosclerosis), with thrombus formation on the disrupted atherosclerotic plaque (atherothrombosis) being a common precipitating factor of ischemic events in patients suffering from these disorders. An evidence-based approach was used to develop a practice guideline, based on available published evidence, for the appropriate utilization of antiplatelet agents (aspirin, ticlopidine, or clopidogrel). These guidelines may be of use to multidisciplinary teams wishing to create or update clinical guidelines or clinical pathways which address the care of patients with atherosclerotic vascular disease. New antiplatelet agents such as clopidogrel may be more effective and associated with lower risk of selected adverse effects (such as gastrointestinal distress, gastrointestinal hemorrhage, and neutropenia) than those previously used to prevent thrombus formation in the setting of atherosclerotic arterial disease. Combination antiplatelet therapy is being evaluated as an option for those patients who experience recurrent events on a single antiplatelet agent.

Effects of nifedipine on myocardial blood flow and systolic function in humans with ischemic heart disease.

OBJECTIVE: To test the hypothesis that, in humans with ischemic heart disease, nifedipine is a primary dilator of the coronary circulation and in general exerts a net positive effect on the balance of myocardial oxygen supply and demand. METHODS: Positron-emission tomography with [13N]-ammonia was used to measure myocardial blood flow in patients at rest, and during infusion of adenosine and ingestion of nifedipine (10 mg capsule, a bite-and-chew technique). Myocardial segments were defined physiologically on the basis of blood flow to adenosine as being normal or having mild, moderate, or severe impairment of dilator reserve. Myocardial systolic function was assessed under comparable physiologic conditions using gated single-photon-emission computed tomography radionuclide ventriculography. RESULTS: Our study population consisted of 13 male patients and one female patient. Ingestion of nifedipine increased heart rate (from 63 +/- 11 to 80 +/- 16 beats/min, P < 0.001) and, as intended, lowered systolic arterial pressure (from 148 +/- 20 to 123 +/- 14 mmHg, P < 0.001) but had no effect on heart rate-pressure product (which changed from 9283 +/- 1576 to 9942 +/- 2162 mmHg/min). Myocardial blood flow in patients at rest in segments with mild, moderate, and severe reductions of dilator capacity (0.63 +/- 0.20, 0.67 +/- 0.25, and 0.58 +/- 0.27 ml/min per g, respectively) was less (P < 0.01) than normal (0.91 +/- 0.29 ml/min per g). Nevertheless, flow of blood was increased versus that at rest (P < 0.01) by infusion of adenosine (to 1.78 +/- 0.13, 1.29 +/- 0.16, and 0.75 +/- 0.22 ml/min per g) and ingestion of nifedipine (to 1.17 +/- 0.51, 1.06 +/- 0.36, 0.85 +/- 0.42 ml/min per g) in segments with mild, moderate, and severe reduction of dilator capacity as well as in normal segments (to 3.18 +/- 0.85 ml/min per g with adenosine and 1.68 +/- 0.65 ml/min per g with nifedipine). Global left ventricular systolic function remained unchanged versus baseline (ejection fraction 0.74 +/- 0.09) with nifedipine (0.76 +/- 0.10). Regional contraction expressed in normalized amplitude units also remained unchanged versus baseline in response to nifedipine. CONCLUSION: Nifedipine increases myocardial blood flow in humans with ischemic heart disease in normal segments as well as in segments with mild, moderate, and severe reductions of dilator capacity, albeit to a lesser extent with increasing impairment of dilator capacity. Both global and regional left ventricular contractile function also are not adversely affected by nifedipine. These improvements in myocardial blood flow in face of no change or a decrease in myocardial demand for oxygen reflect an overall favorable effect on the balance between the supply of and demand for myocardial oxygen.

Overall cardiovascular profile of sildenafil citrate.

Sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE5), is the first in a new class of orally effective treatments for erectile dysfunction. During sexual stimulation, the cavernous nerves release nitric oxide (NO), which induces cyclic guanosine monophosphate (cGMP) formation and smooth muscle relaxation in the corpus cavernosum. Sildenafil facilitates the erectile process during sexual stimulation by inhibiting PDE5 and thus blocking the breakdown of cGMP. Sildenafil alone can cause mean peak reductions in systolic/diastolic blood pressure of 10/7 mm Hg that are not dose related, whereas the heart rate is unchanged. Sildenafil and nitrates both increase cGMP levels in the systemic circulation but at different points along the NO-cGMP pathway. The combination is contraindicated because they synergistically potentiate vasodilation and may cause excessive reductions in blood pressure. Erectile dysfunction is a significant medical condition that shares numerous risk factors with ischemic heart disease, and hence a substantial overlap exists between these patient groups. From extensive clinical trials, the most commonly reported cardiovascular adverse events in patients treated with sildenafil were headache (16%), flushing (10%), and dizziness (2%). The incidences of hypotension, orthostatic hypotension, and syncope and the rate of discontinuation of treatment due to adverse events were <2% and were the same in patients taking sildenafil and those taking placebo. Retrospective analysis of the concomitant use of antihypertensive medications (beta blockers, alpha blockers, diuretics, angiotensin-converting enzyme inhibitors, and calcium antagonists) in patients taking sildenafil did not indicate an increase in the reports of adverse events or significant episodes of hypotension compared with patients treated with sildenafil alone. In clinical trials, the incidence of serious cardiovascular adverse events, including stroke and myocardial infarction, was the same for patients treated with sildenafil or placebo. Concurrent disease states, such as renal or hepatic impairment, or concomitant use of inhibitors of the cytochrome P450 isozyme CYP3A4 could increase systemic exposure to sildenafil. Since the US market launch in April 1998, monitoring of spontaneous adverse event reports in association with sildenafil has demonstrated a pattern that is generally consistent with the experience observed during clinical development, with the exception of infrequent reports of priapism. In conclusion, extensive clinical testing has shown that overall treatment with sildenafil for up to 1 year is well tolerated and is associated with a low incidence of adverse events that result in discontinuation of treatment in <3% of patients.

Are there differences among angiotensin receptor blockers?

Pharmacologic effects of specific drugs are frequently attributed to their therapeutic class because all agents within a particular class have the same mechanism of action. Because "head-to-head" comparisons in trials are rare, any differentiation between drugs of the same class is usually limited to comparisons of their pharmacokinetic profiles, and it is usually assumed that most of the drugs in a therapeutic class have similar efficacies. Two recent randomized clinical trials demonstrated that the antihypertensive agents irbesartan and losartan, both angiotensin receptor blockers, are not equally effective in reducing blood pressure among patients with hypertension. In both a fixed-dose trial and a titration-protocol trial, patients treated with irbesartan achieved a greater reduction in blood pressure than did those treated with losartan. The response rate was also higher among patients treated with irbesartan. Therefore, irbesartan, used either alone or as a component of response-based combination therapy with a diuretic, is a more potent antihypertensive agent than losartan. These results and the previously published pharmacologic profiles of these drugs demonstrate that angiotensin receptor blockers are, like many other classes of antihypertensive agents, more different than alike.

R-PEP-27, a potent renin inhibitor, decreases plasma angiotensin II and blood pressure in normal volunteers.

The hemodynamic and humoral effects of the specific human renin inhibitor R-PEP-27 were studied in six normal human subjects on low and high sodium intake diets. An intravenous infusion of R-PEP-27 (0.5 to 16 micrograms/min/kg body wt) reduced blood pressure in a dose-dependent fashion; the mean arterial blood pressure at the end of the infusion fell from 128 +/- 4/83 +/- 4 to 119 +/- 3/71 +/- 3 mm Hg (mean +/- SEM) (P < .01) during the low sodium intake diet. R-PEP-27 had no effect on blood pressure during the high sodium intake diet. R-PEP-27 significantly reduced plasma angiotensin II and aldosterone concentrations. The temporal response to R-PEP-27 suggests that it is a short-lived although highly potent competitive inhibitor of renin; this peptide is a valuable and specific physiologic probe of the renin-angiotensin system.

Angiotensin-converting enzyme inhibitors: more different than alike? Focus on cardiac performance.

Development of an increased systemic vascular resistance and the concomitant increase in blood pressure are associated with significant changes in left ventricular structure and function. The plasma and tissue renin-angiotensin systems play an important, but variable, role in the regulation of blood pressure and systemic vascular resistance in normotensive and hypertensive patients. Non-angiotensin-mediated effects of angiotensin-converting enzyme (ACE) inhibitors and/or differential tissue specificities may result in a variable hemodynamic response to individual therapies. Using first-pass radionuclide cineangiography, the hemodynamic effects of captopril, lisinopril, and fosinopril were compared. Fosinopril induced a greater reduction in systemic vascular resistance than did equipotent hypotensive doses of captopril or lisinopril and was associated with an increase in cardiac output, left ventricular peak ejection rate, and left ventricular peak filling rate. Along with previously accumulated data, these results suggest that structural differences among ACE inhibitors may result in unique physiologic effects. Fosinopril appears to have a cardiotropic effect that causes improved left ventricular diastolic performance; this effect is unique among currently available ACE inhibitors. The clinical significance of the unique profiles of individual ACE inhibitors awaits assessment via comparative clinical investigations.

Total aortic occlusion caused by sustained balloon inflation: a previously unreported complication of intraaortic balloon counterpulsation.

A case of acute lower-body ischemia 2 days following intraaortic balloon pump insertion is reported. Fluoroscopy revealed persistent balloon inflation throughout the cardiac cycle with distal aortic occlusion. Attempts to manually deflate the balloon were unsuccessful until a guidewire was advanced through the gas-exchange lumen into the body of the balloon. The balloon catheter was removed without clinical sequelae other than transient oliguria and an asymptomatic increase in creatinine phosphokinase (CPK). This is a previously unreported complication of intraaortic balloon counterpulsation.

Bepridil improves left ventricular performance in patients with angina pectoris.

Patients with coronary artery disease and angina pectoris have abnormalities of left ventricular (LV) diastolic performance. These abnormalities, which exist when the patients are at rest and not experiencing angina, are presumably secondary to abnormalities of intracellular calcium metabolism. Twenty-three patients with chronic exertional angina pectoris participated in a placebo-controlled, randomized, cross-over trial of bepridil hydrochloride. Angina frequency, nitroglycerin (NTG) consumption, and treadmill exercise capacity were assessed, and each patient underwent first-pass radionuclide cineangiography while receiving placebo or bepridil to assess LV performance. Bepridil decreased angina frequency from 8.5 +/- 0.6 to 4.4 +/- 1.5 episodes per week (p < 0.01) and NTG consumption from 7.2 +/- 2.4 to 3.6 +/- 1.5 tablets per week (p < 0.01). Total treadmill exercise time, time to onset of angina, and time to 1-mm ST segment depression increased significantly during bepridil therapy. Cardiac output (CO), stroke volume (SV), and ejection fraction (EF) increased at rest and during peak upright bicycle exercise. Peak ejection rate and peak filling rate increased, and time to peak ejection rate and time to peak filling rate decreased at rest and at peak exercise during bepridil therapy. In addition, early diastolic filling fraction increased and atrial filling volume decreased during bepridil treatment. Bepridil is effective as monotherapy for treatment of patients with exertional angina; its use is associated with increased exercise capacity and decreased angina frequency and NTG consumption as well as improved LV systolic and diastolic performance at rest and during peak exercise.

Comparison of the cardiac and hemodynamic effects of lisinopril and atenolol in patients with hypertension: therapeutic implications.

The antihypertensive and hemodynamic effects of lisinopril and atenolol were evaluated in 21 patients with mild-to-moderate essential hypertension. Left ventricular systolic and diastolic performances were assessed prior to and following treatment by first-pass radionuclide cineangiography at rest and during peak upright bicycle exercise. Both lisinopril and atenolol treatment significantly reduced the blood pressure. Lisinopril therapy was associated with a reduction in systemic vascular resistance and left ventricular end-diastolic and end-systolic volumes but no change in stroke volume, cardiac output, peak ejection rate, peak filling rate, time to peak ejection rate, or time to peak filling rate. In contrast, atenolol therapy was associated with an increase in end-diastolic volume and stroke volume but no change in cardiac output; the left ventricular peak ejection and peak filling rates were decreased by atenolol treatment. Although both lisinopril and atenolol each significantly reduced the blood pressure, lisinopril had no effect on left ventricular systolic or diastolic performance; in contrast, atenolol decreased both systolic and diastolic parameters of ventricular performance. Left ventricular function may be affected in significantly different ways despite apparent similarities in blood pressure control in patients who respond to angiotensin converting enzyme inhibition or beta-adrenergic receptor blockade. Differences in hemodynamic response to an antihypertensive agent may be important in the selection of a drug for the treatment of subsets of patients with cardiac function abnormalities.

Effects of fosinopril on cardiac function in patients with hypertension. Radionuclide assessment of left ventricular systolic and diastolic performance.

Numerous pharmacologic agents are capable of lowering the blood pressure of hypertensive patients; however, each drug has a characteristic side effect profile and effect on cardiac performance. In this study, the hemodynamic effects of the angiotensin converting enzyme inhibitor fosinopril were assessed at rest and at peak upright bicycle exercise by first-pass radionuclide cineangiography in 12 patients with essential hypertension. Fosinopril reduced blood pressure at rest in the seated position from 152/101 to 131/85 mm Hg (P less than .01) and at peak exercise from 206/103 to 184/91 mm Hg (P less than .01). Fosinopril therapy was associated with an increase in stroke volume and cardiac output and a decrease in systemic vascular resistance at rest and during peak exercise. Both peak ejection rate and peak filling rate increased significantly at rest during fosinopril therapy. The unique cardiotropic response to fosinopril may reflect its effects on the myocardial renin-angiotensin system, and suggests that this agent may offer a therapeutic advantage compared with other angiotensin converting enzyme inhibitors.