	In this era of an aging population, drug—drug and drug–disease interactions, and increasing numbers of medical therapies, polypharmacy is the rule, not the exception. As pointed out in the excellent review by Berensen and Weart (page 27), polypharmacy can be associated with adverse reactions, decreased efficacy, decreased adherence, and greater cost. Of course, when appropriate, polypharmacy may also improve a patient’s quality of life and adherence to treatment, and thereby improve morbidity and mortality.

	So how can one enhance the good and reduce the bad? Berensen and Weart provide a number of recommendations, including keeping medication regimens simple and partnering with a pharmacist. One other recommendation I might add is to insist that patients bring with them to each visit all medications: pills and liquids, prescription and nonprescription, bought in either

	a pharmacy, food market, or health food store. The physician or staff should then record these in the patient’s chart on each visit and address possible drug interactions.

	One approach to simplifying polypharmacy is the use of combination tablets, an approach criticized years ago and still (although less so) controversial today. The problem with combination tablets 10 or more years ago included the fact that most medications had many titration steps, and it was difficult to come up with combination tablets that had the necessary doses for a specific patient; another issue was that older drugs were associated with more adverse effects, and it was difficult to determine which medication in the combination tablet was causing a problem. SerApEs was a classic example of one of the older combination tablets. It contained three separate drugs—reserpine, apresoline, and esidrex&mdash;and it was a very effective antihypertensive medication. Modern-day medications have a narrower titration range and fewer side effects. There are a number of examples of two medications in one tablet. For hypertension, for example, there are a number of agents, eg, beta blocking agents, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, etc, combined with a diuretic. The combination of amlodipine besylate and benazepril hydrochloride (Lotrel®) is an example of two antihypertensive agents, other than a diuretic, in a combination pill. Another approach is the use of a combination pill that addresses two distinct diseases that commonly occur together. The recent release of a combination tablet containing amlodipine besylate and atorvastatin calcium (Caduet®), in recognition of the frequent association of dyslipidemia with hypertension, is one example. This recent entry may represent the beginning of the “polypill” era. Indeed, there has been a recent flurry of editorials regarding the concept of a polypill&mdash;a proposed tablet that would contain an HMG-CoA reductase inhibitor (statin), three antihypertensive agents at half dose, aspirin (75 mg), and folic acid; this combination of six medications in one tablet could be indicated for most patients with hypertension. Then, instead of six pills, polypharmacy would be achieved with one tablet in which the prospect for drug—drug interactions would be minimal.

Articles

Cardiology Review Online

Polypharmacy%u2014the good, the bad,  and the ugly

	Nannette M. Berensen, PharmD  •  C. Wayne Weart, PharmD

	From the Department of Pharmacy and Clinical Sciences and the Department of Family Medicine, Medical University of South Carolina, Charleston, South Carolina

	In 2000, there were 35 million people aged 65 years or older living in the United States, a 12% increase compared with data from 1990.1 Those who reach age 65 can expect to live another 15 to 19 years.1 As a group, the elderly purchase and consume more prescription and over-the-counter (OTC) medicines than any other age group.2,3 This is not surprising, considering that elderly people take an average of four to five medications at any given time. The effects of aging make this age group particularly vulnerable to adverse drug events.4,5 Mannesse and colleagues found that one in six older patients admitted to a general medicine floor had an adverse drug reaction, and 25% had serious drug reactions.6 Polypharmacy, therefore, assumes increasing importance in the day-to-day management of this population.

	Major polypharmacy generally refers to using five or more medications concurrently; the term also applies to any medication regimen that contains any unnecessary medications.7-9 The potential consequences of polypharmacy include adverse drug reactions, drug interactions, medication errors, decreased medication adherence, increased costs, and increased consumption of health care services.

	Polypharmacy should not be confused with justifiable augmentation therapy, for example, adding a diuretic to a patient’s beta-blocking agent regimen if blood pressure is not controlled. Using multiple medications that have different and complementary mechanisms is deemed necessary and advocated in various treatment guidelines, such as for congestive heart failure (five medications), the treatment of Helicobacter pylori (three medications), and type 2 diabetes (two or more antidiabetic agents).10-12

	Information overload without meaningful education. Direct-to-consumer pharmaceutical advertising in print, on television, and on the Internet is unprecedented. It is common for patients to request medications by name during office visits. Fueling this behavior are the patients’ strong beliefs that medications make people well and are indeed necessary. Although many patient education databases, textbooks, and company-sponsored educational materials are available, most patients appear to have no better understanding of their medication regimens today than they did 20 years ago. This is probably because most physicians and pharmacists do an inadequate job of explaining medication regimens. Moreover, patients are often not educated frequently enough

	To test this point, ask 10 patients with asthma to demonstrate their metered-dose inhaler technique.

	Incomplete assessments, responses, and documentation. Incomplete history taking or incomplete documentation in the medical record by health care professionals, especially regarding changes in dosage, medication schedules, or medication discontinuations, contributes to polypharmacy. It is essential to specifically ask the patient if other practitioners have evaluated them since their last visit and to determine if they are taking additional medications or have had their regimen otherwise altered.

	Poor adherence to and lack of persistence with medication regimens also contributes to poly-

	pharmacy. Consider a patient with asthma who was prescribed the AdvairDiskus® 100/50 (a combination of 100 µg of fluticasone and 50 µg of salmeterol) and an albuterol inhaler for rescue. At her 6-month follow-up visit, the patient reports that she is still having frequent exacerbations. The physician decides to prescribe the AdvairDiskus® 250/50, twice daily, and calls in the prescription by phone to the patient’s pharmacy. On consulting with the pharmacist, the physician learns that the patient had only refilled the Advair- Diskus® 100/50 once in the last 6 months, but refilled her albuterol inhaler 22 times during the same period.

	Patients may also provide incomplete responses when asked about their medication use. If patients are not properly educated about their medications to begin with, it is unlikely that they will be good historians. Many patients believe that OTC medications, vitamins, and herbal preparations are harmless and, therefore, they do not mention these products. Prescribers are encouraged to specifically solicit this information in a supportive manner when taking a medication history. Although a prescriber may not want the patient to use certain OTC or herbal preparations for valid clinical reasons, patients need to feel comfortable discussing this type of information with their physicians.

	Pharmacy-order entry data provide limited information and are no substitute for a face-to-face medication history. These data may reveal information about prescriptions filled at a specific location only and afford little information regarding efficacy, tolerability, or safety. They also do not allow the clinician to determine if a patient is taking the medications as the prescribers intended. Unintended polypharmacy may result from prescribers using trade or brand names for combination products; hence, the prescriber may be unaware of all the active ingredients contained in the preparation.

	Automatic therapeutic substitution programs. It is increasingly common for health care organizations to use automatic therapeutic substitution (ATS) programs. These programs provide authorization for phar-macists to substitute a formulary

	medication in place of an ordered nonformulary medication without having to contact the prescriber. ATS protocols have been deemed to be therapeutically equivalent and have been sanctioned by the organization’s medication use governing body (eg, the pharmacy and therapeutics committee). Although ATS programs are intended to minimize nonformulary use, inadequate patient or caregiver education may result in unintended therapeutic duplication, further contributing to polypharmacy. Consider the following scenario. A patient is admitted to a hospital that uses ATS protocols for various medication classes (eg, proton pump inhibitors, angiotensin-converting enzyme [ACE] inhibitors). Before admission, the patient was taking lansoprazole and enalapril. Based on the institution’s ATS protocols, pantoprazole is substituted for lansoprazole and benazepril is substituted for enalapril during the patient’s hospitalization. A few days later, the patient is discharged with prescriptions for pantoprazole and benazepril. One week later, the patient is admitted to the emergency department. His wife states that he had been complain-

	ing of dizziness and had fainted when getting up from the breakfast table. When questioned about his medications, she says that he had been taking lansoprazole, enalapril, pantoprazole, and benazepril. It is essential that patients and caregiv-ers receive adequate discharge and medication counseling to prevent this situation from occurring.

	Aging. As part of the normal aging process, people experience changes in organ function. After age 40, for example, creatinine clearance dereases by about 6.5 mL/min per decade based on 1.73 m2 body surface area.13 Normal aging also results in decreased hepatic and biliary function and changes in pharmacodynamics; for many medications, there appears to be an increase in the sensitivity of receptors.6 These age-related changes, often complicated by other comorbidities, set the stage for problems with polypharmacy. Prescribers may find the revised Beers Criteria for Potentially Inappropriate Medication Use in Older Adults helpful in deciding which medications to avoid altogether and which to avoid based on a patient’s concomitant diseases or conditions.14

	drug interactions may have a pharmacokinetic or pharmacodynamic basis. A pharmacokinetic interaction results when the effect of one medication alters the absorption, distri-bution, metabolism, or elimination

	of another. Of interest, changes in protein binding attributed to age generally do not significantly affect drug disposition.15 A pharmacodynamic interaction may result when the synergism or antagonism of one agent exhibits a pharmacologic effect that would not be expected with either drug alone. Malone and colleagues conducted a cross-sectional evaluation to create a list of clinically important drug—drug interactions commonly encountered in the ambulatory and community pharmacy settings.16 An expert panel that consisted of two physicians, two pharmacists, and a drug-interactions expert systemically reviewed standard drug interaction references and primary literature, and developed a list of 25 drug–drug interactions that are clinically important.

	More medications available. At present, there are over 10,000 prescription medications available in the United States, and that number is rising.17 According to a recent survey by the Pharmaceutical Research and Manufacturers Association, pharmaceutical and biotechnology companies have more than 800 medicines in development to better manage diseases common in the elderly, including Alzheimer’s disease, arthritis, cancer, heart disease, osteoporosis, Parkinson’s disease, and stroke.18 In addition, there are more than 100,000 OTC products currently marketed, encompassing about 800 active ingredients and more than 80 therapeutic categories.17

	Compliance/adherence/persistence. Col and colleagues reported that as many as 11.4% of hospital admissions are attributed to poor medication compliance.19 Medication adherence following hospitalization is also of concern. A study evaluating this issue in 50 patients recently discharged from a hospital showed that, within 2 weeks of discharge, more than 20% of patients had deviated from the prescribed regimen.20 Regimen complexity appeared to be a factor affecting compliance. Fewer than 25% of the patients knew the names and purposes of their medications, and 70% could not state one side effect that their medications might cause. More recently, Barat and colleagues evaluated data from 348 patients who were aged 75 years.21 Although they reported that 60% of patients knew the indication for at least 75% of their medications, only 21% understood the consequences of omitting a drug or dose. Perhaps more concerning, the data showed that only 4% of patients had any knowledge of adverse effects.

	Patient education. To achieve optimal outcomes, patients must understand their disease states and medications. Patient education is critical to achieving this goal. Health care professionals should assume that patients have not been adequately educated unless they can prove otherwise. Until clear delineation for the responsibility of patient education is achieved, this assumption is in the patient’s best interest.

	Patients who are elderly, cognitively impaired, mentally ill, blind, deaf, aphasic, or do not speak English may require additional efforts regarding patient education. Several aids can be used to facilitate patient understanding and improve medication adherence. Prefilled pillboxes make it easier for elderly patients to take the right medications at the right times. Pillboxes are easy to handle and do not require a high degree of manual dexterity. Most pharmacists are willing to fill pillboxes for their patients. Caution must be taken to prevent unintentional ingestion, because these devices usually do not have poison-prevention closures.

	Charts detailing the purpose, dose, schedule, and common side effects of each medication can be created and posted on the patient’s refrigerator to serve as a daily reinforcement of the patient’s regimen. Instructions on what to do if the patient experiences an adverse effect and information on what to do if a dose is missed should be included. Additionally, patients and health care providers benefit from patients having an up-to-date medication list. The provider should review this at every patient encounter. Patients need to be instructed to always bring their lists of medications or a bag containing all of the medications they are currently taking, or both, to each health care appointment. Medication pamphlets used during a patient counseling session, if they are written appropriately, may be a useful future reference for the patient.

	Clinical strategies. Several approaches can help avoid the use of multiple drugs and minimize their side effects, especially in the elderly.

	•    Use nonpharmacologic therapy first. To illustrate this concept, consider the conditions of insomnia and gastroesophageal reflux disease. Insomnia is a symptom, not a disease. Treating the underlying cause, such as anxiety, depression, gastroesophageal re-flux disease, diabetes mellitus, congestive heart failure, or pain, will generally eliminate insomnia. The physician needs to ensure that good sleep hygiene has been adequately tried. Patients suffering from gastroesophageal reflux disease should be instructed to raise the head of their bed

	or to use a wedge pillow. Patients should also be advised to avoid lying down within 3 hours after

	•    Select medications that do not have active metabolites. For example, if a benzodiazepine is indicated, choose lorazepam, oxazepam, or temazepam instead of diazepam. In general, avoid prescribing agents that have long half-lives. A physician wishing to prescribe chlorpropamide for a 72-year-old patient with type 2 diabetes with an estimated creatinine clearance of 50 mL/min should reevaluate this choice. Chlorpropamide has a terminal half-life of about 36 hours, is eliminated 100% renally, may cause dilutional hyponatremia, and can result in prolonged hypoglycemia. Furthermore, a decreased glomerular filtration rate may prolong the half-life to more than 72 hours. In contrast, glipizide has a terminal half-life of approximately 2 to 4 hours, is eliminated 80% renally, and has no active metabolites. It also has a lower risk of weight gain and hypoglycemia compared with other sulfonylureas.

	•    Keep medication regimens simple. Regimen complexity is a major factor in compliance. Although decreasing the number of medications is not always possible, the scheduling of those medications can usually be arranged to result in fewer administration times per day. When appropriate, consider prescribing combination products. If you have a patient who is taking 10 mg of enalapril and 25 mg of hydrochlorothiazide, consider prescribing Vaseretic® 10-25. There are many generic combination products available. In addition to reducing the patient’s pill burden, this will also eliminate an insurance copayment.

	•    Give medications an adequate trial before increasing doses, changing agents, or adding drugs to the regimen. For example, if you initiate treatment with a selective serotonin reuptake inhibitor for a patient suffering from depression, 4 to 6 weeks are needed to see the maximum effect of therapy.

	•    Eliminate any medication that does not have a current therapeutic indication. For example, continuing to prescribe a histamine2 antagonist when the patient is on a proton pump inhibitor is not rational prescribing.

	•    Be aware of multiple-ingredient preparations, especially those sold over the counter. It is not uncommon for cold and flu preparations to have four or five active ingredients. Consider a patient with osteoarthritis who is taking 1 g acetaminophen four times daily and develops a cold. While grocery shopping she purchases a cold and cough flu medication. She begins taking one packet every 6 hours for the next 5 days. Each packet of this product contains 650 mg of acetaminophen,

	4 mg of chlorpheniramine maleate, 20 mg of dextromethorphan hydrobromide, and 60 mg pseudoephedrine hydrochloride. By using this cold preparation, the patient unknowingly ingests well above the maximum daily dose of acetaminophen.

	•    When possible, avoid treating adverse drug events with additional medications because the masking of side effects that may occur with additional agents perpetuates polypharmacy. Switching medications may be the best option. For example, rather than adding a stimulant laxative to the regimen of a patient who develops constipation while taking verapamil for hypertension, consider changing to diltiazem. Diltiazem is equally effective in controlling blood pressure and heart rate but has much less constipation associated with it.

	•    Partner with pharmacists who want to meet your drug information needs. Encourage them to keep you informed about your patients who they suspect are not adhering to their regimens, especially when nonadherence is caused by a patient’s inability to afford what you have prescribed. Pharmacists can also provide patients with intensive counseling regarding disease states and medications to reinforce or supplement the information that

	the physician has provided. In addition, pharmacists play a pivotal role in informing patients about and assisting patients with medication assistance programs. Pharmacists can also help patients with compliance aids, including pillboxes or medication scheduling charts.

	•    Use a drug information center when the need for information

	is complex. Drug information centers are designed and staffed to assist physicians, pharmacists, and nurses in managing patients’ pharmacotherapy regimens. Many centers provide services to practicing health care professionals free of charge. A listing of the major drug information centers can be found in the 2004 Physicians’ Desk Reference and Drug Topics Redbook.

	Polypharmacy is a complex issue because underprescribing can be as problematic as overprescribing.22-24 A recent study by Higashi and colleagues further supports this point.25 These investigators evaluated 43 quality indicators spanning four pharmacologic care domains in vulnerable elderly patients from two managed care organizations: (1) prescribing indicated medications; (2) avoiding inappropriate medications; (3) education, continuity, and documentation; and (4) medication monitoring. Of the 475 vulnerable patients identified, 372 had medical records that could be abstracted. In this study, the term vulnerable elders was defined as persons at least 65 years of age who were at increased risk of death or functional decline. The pass rate for avoiding inappropriate medications was favorable

	[CI], 96%—98%). In contrast, the pass rates in the other domains were as follows: prescribing indicated medication, 50% (95% CI, 45%–55%); education, continuity, and documentation, 81% (95% CI, 79%–84%); and medication monitoring, 64% (95% CI, 60%–68%).

	When treating patients with chronic diseases or comorbidities, polypharmacy may be required to achieve optimal outcomes. Consider the case of a 66-year-old woman with type 2 diabetes, hyperlipidemia (total cholesterol, 150 mg/dL), and hypertension.26 In combination with diet and exercise, it is likely this patient will require two or more agents to achieve the goals of glycemic control (fasting blood glucose level between 80 and 100 mg/dL, A1C level below 6%; 1- to 2-hour postprandial glucose level below 180 mg/dL, and a bedtime glucose concentration between 100 and 140 mg/dL). The patient should receive an ACE inhibitor or an angioten-

	sin-II receptor antagonist to prevent diabetic nephropathy. The patient may also require a second or third agent to reach the recommended goal blood pressure of less than 130/80 mm Hg. To reduce the risk of cardiovascular events based on this patient’s baseline total cholesterol concentration, it would also be appropriate to treat her with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) to achieve a low-density lipoprotein (LDL) cholesterol reduction of approximately 30% regardless of baseline LDL. The patient would also be taking 81 to 162 mg of aspirin daily. To treat this common triad of conditions according to current guidelines, seven medications are needed.26

	Helping patients afford their medications

	Patients frequently express concern regarding their inability to afford medications. This is particularly true for regimens consisting of multiple agents. Physicians are encouraged to be mindful of medication cost at the time of prescribing. Generic preparations should be used whenever available. With the new Medicare-approved drug discount card, patients are likely to be more confused than ever. Physicians can play a significant role in teaching patients or their caregivers how to get the greatest value in health care. By calling 1-800-Medicare or by logging on to www.medicare.gov, providers, patients, and their caregivers can compare approved providers and enrollment fees and can obtain cost quotes for a 30-day supply of their medications.27 The table shows 5 of 34 discount programs available for 10 mg of atorvastatin daily and the pharmacies within a 3.5-mile radius of the zip code 29466. Although patients can only enroll in one Medicare-approved drug discount card plan, it is important for them to know that they may also use their non—Medicare-approved discount cards (eg, Together Rx, Pfizer Share Card, or Lilly Cares Card).

	Reviewing the costs associated with adverse drug reactions assists in understanding the costs associated with polypharmacy, which is a risk factor for adverse drug reactions.5,28 In the outpatient population, adverse drug reactions of all severity have been reported to occur in 32% of patients.5 Medication-related morbidity and mortality in this setting is estimated to cost $76.6 billion annually.29 In a meta-analysis, Lazarou and colleagues estimated that 6.7% of inpatients experience serious adverse drug reactions.30 Annual costs attributed to adverse drug reactions in hospitalized and nursing home patients have been calculated to be $20 billion and $4 billion, respectively.31,32

	Poor medication management resulting in polypharmacy has significant resource implications for the health care, social, and private sectors. Although the issue is complex, solutions are not beyond reach. There is little doubt that medications allow patients to live longer, healthier, and more productive lives. The goal is not to eliminate polypharmacy but rather to achieve balanced and rational prescribing to optimize patient outcomes.

Managing  polypharmacy issues

	Both the incidence and prevalence of hypertension, primarily systolic hypertension, rise with advancing age in nearly all Western industrialized societies, so that nearly two thirds of men and women older than 65 years can be classified as hypertensive; however, just because the prevalence of hypertension in the elderly is ubiquitous does not mean that it is innocuous. Data from the Framingham Heart Study1 and other studies have documented the role of hypertension, particularly isolated systolic hypertension, as the dominant risk factor for an extensive array of adverse cardiovascular outcomes at an advanced age, including coronary heart disease (CHD) events, stroke, and heart failure. Elevated systolic blood pressure, especially if untreated, is a key risk factor for cognitive impairment at an advanced age, leading to vascular dementia. A strong case can be made for the effective management of hypertension at all ages; however, this problem requires special clinical attention in elderly patients.

	In this context, the article by Otieno and Gradman (page 14) provides an excellent review of the epidemiology, pathophysiology, and treatment options for hypertension in the elderly, which should be useful for a wide spectrum of health professionals, including primary care physicians, internists, nurse practitioners, and cardiologists who manage this condition in older persons.

	Based on the results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)2 and a number of other clinical trials,3 a diuretic is still the most well-established and well-validated initial drug option for the management of hypertension in the elderly. Diuretics, although inexpensive and usually well tolerated in older persons, at times may significantly exacerbate, to the point of intolerance, symptoms of frequency and nocturia in men with benign prostatic hyperplasia and stress incontinence in women. Effective management of blood pressure in this population frequently requires more than one drug. The second drug chosen in this clinical situation usually is a beta-adrenergic blocking agent. Beta blockers are well tolerated by most patients, but may cause fatigue and, in some instances, symptomatic bradyarrhythmias.

	Of interest, several more recent clinical trials referenced by the authors, including the Systolic Hypertension in Elderly in Europe (Syst-Eur) trial, the Shanghai Trial of Nifedipine in the Elderly (STONE), the Swedish Trial in Old Patients with Hypertension-2 (STOP-2), and the Losartan Intervention for Endpoint Reduction (LIFE) trial, have now confirmed the efficacy and safety of calcium channel blocking agents, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, alone or combined with other drugs for the management of hypertension in an advanced age group. Antihypertensive drugs in these classes, although considerably more expensive than diuretics and beta blockers, broaden the therapeutic armamentarium to include the majority of agents now used in middle-aged and younger persons in the management of hypertension. In addition to substantial reductions in cerebrovascular events and congestive heart failure, most intervention studies of drug therapy in older persons have consistently demonstrated either beneficial trends or significant reductions in CHD events and mortality for hypertension.4 Such findings appear to be considerably less prominent in clinical trials of predominantly middle-aged hypertensive patients.

	Developing an effective regimen of antihypertensive drugs that meets

Hypertension in the elderly:  Ubiquitous but not innocuous Pantel S. Vokonas, MD 

	Carotid angioplasty and stenting is an emerging technology under investigation for the treatment of carotid bifurcation stenosis. Advocates point to its minimally invasive nature and studies showing results comparable to some published surgical series. Detractors emphasize that carotid angioplasty and stenting is an evolving technology whose purpose is to supplant an established, highly scrutinized and safe operation that has excellent results and low morbidity. All agree, but may not admit, that issues of turf, economics, and marketing have assumed dominance over patient safety in the current environment.

	The Achilles’ heel of carotid angioplasty and stenting, similar to carotid endarterectomy, is periprocedural neurologic events. Neuroprotective devices have been developed to address this issue, and have reduced clinically apparent neurology deficits after carotid angioplasty and stenting.1 However, these devices have limitations, as shown by Schofer and Tübler (page 41). Emboli can occur during manipulations in the aortic arch, cannulation of the carotid artery, dilation of the stenotic lesion, and passage and retrieval of the protection device. The contralateral lesions seen on magnetic resonance imaging (MRI) reported by Schofer and Tübler most likely resulted from manipulation of the aorta and arch vessels rather than from the carotid angioplasty and stenting itself. Furthermore, distal neuroprotective devices do not trap all particles. Conceptually, the technique of flow reversal as described by Ohki and colleagues may offer the best protection from embolization during carotid angioplasty and stenting.2

	Diffusion-weighted MRI is the most sensitive technology currently available for detecting cerebral ischemia, and lesions are often asymptomatic. The long-term implications of these asymptomatic lesions are unpredictable at the present time; however, they raise concerns, particularly in patients with asymptomatic stenosis. Data on diffusion MRI after carotid endarterectomy are scarce, so comparisons are difficult.

	Carotid angioplasty and stenting will remain a technique indicated in some patients with carotid bifurcation disease. Its clearest indications are in patients with difficult carotid anatomy (high lesion) or a “hostile neck,” and in neurologically symptomatic patients with severe cardiac comorbidities. There are also clear situations in which carotid angioplasty and stenting is associated with increased technical difficulties and morbidity; most relate to problems with femoral access, evidence of aortic arch atheroma and tortuous arch vessels, and unstable or highly echolucent plaque. The role of carotid angioplasty and stenting in asymptomatic carotid stenosis, currently the primary indication for intervention in most series, remains to be established by prospective randomized trials. It cannot be extrapolated from data on carotid endarterectomy. However, it is likely that both techniques will be effective in a large number of patients.

	As physicians dedicated to the care of patients with cerebrovascular disease, we are obligated to adapt the treatment to the patient, rather than the patient to the treatment, or to our own prejudices and abilities. Proper studies comparing carotid angioplasty and stenting to carotid endarterectomy, employing patient stratification on the basis of vascular anatomy, plaque character, and patient characteristics are needed to preserve the patient’s best interest.

Carotid artery stents:  Benefits and challenges John J. Ricotta, MD

	An asymptomatic 73-year-old man was scheduled for carotid stenting because of a progressive 90% stenosis of the right internal carotid artery. His risk factors included hypertension, previous smoking, and diabetes. He had no history of any major serious illnesses, and his left ventricular function was normal.

	Preprocedural antithrombotic treatment consisted of aspirin and clopidogrel. Carotid access was accomplished through a No. 6 French sheath over a No. 4 French Berenstein (J & J Cordis, Miami, Florida) catheter. After sheath placement, heparin was administered, and a 5.0-mm Spider Filter (ev3Inc., Plymouth, Minnesota) was positioned. A self-expanding 8.0/40-mm Conformexx stent (C.R. Bard Inc., Murray Hill, New Jersey) was placed across the lesion, followed by postdilation at 6 atm with a 5.0/20-mm balloon. The Spider Filter was subsequently retrieved, showing no visible particles. The procedure was well tolerated by the patient, and the postprocedural neurologic examination was normal. On postprocedural diffusion-weighted magnetic resonance imaging (MRI) performed 16 hours after the procedure, however, a new focal lesion was detected (figure). Despite this cerebral ischemic event, the patient remained free of obvious neurologic symptoms. 

Case report: Carotid artery stenting in a  73-year-old man

	From the Center for Cardiology and Vascular Intervention, Hamburg, Germany

	Carotid artery stenting has emerged as an alternative to endarterectomy for the treatment of carotid artery stenoses. Neuroprotective devices have been developed to help reduce the risk of stroke caused by procedure-related distal embolization. Diffusion-weighted magnetic resonance imaging (MRI) is a highly sensitive tool for the detection of cerebral ischemia. In unprotected carotid artery stenting preceded by three- or four-vessel cerebral angiography, silent cerebral ischemia was found in 37% of cases1 compared with only 25% of patients who underwent protected carotid artery stenting using the AngioGuard (J & J Cordis, Miami, Florida) filter device.2

	In the present study, the incidence of cerebral ischemia was assessed using serial MRI in an unselected, consecutive patient cohort that underwent protected carotid artery stenting with a variety of devices without preceding diagnostic angiography.

	Of 50 consecutive patients who underwent carotid artery stenting at our institution, 42 consented to pre- and postinterventional MRI scanning of the brain. A total of 44 procedures were performed, corresponding to 44 hemispheres treated.

	Protection devices. The cerebral protection systems used were the second- and third-generation NeuroShield (Abbott Vascular, Redwood City, California; n = 14), the FilterWire (Boston Scientific, Natick, Massachusetts; n = 14), the TRAP (Microvena Corporation, Plymouth, Minnesota; n = 11), the AngioGuard (n = 2), the Distal Protection Device (Medtronic AVE, Santa Rosa, California; n = 2), and the endovascular clamping device (MO.MA®, Invatec, Roncadelle, Italy; n = 1).

	Carotid artery stenting procedure. At least 3 days prior to the intervention and until 4 weeks after the intervention, patients were treated with clopidogrel, 75 mg daily, and aspirin, 100 mg daily. Carotid artery stenting was performed with a 100-cm No. 5 French Vitek catheter (Cook, Bloomington, Indiana) and a No. 7 French long introducer sheath or the No. 11 French MO.MA system (in one patient). All patients were given a bolus of heparin, 70 to 100 IU/kg. The protection systems were placed, and the lesions were predilated. A self-expanding stent was deployed (predominantly using Wallstents, Boston Scientific), and the lesions were postdilated.

	Magnetic resonance imaging. Within 24 hours before and after the intervention, MRI scans were taken in identical, single-shot, echoplanar sequences. The areas covered by hyperintensive foci were calculated, and patients with positive results were asked to undergo follow-up MRI scanning 3 to 6 months after the intervention. A calculation of the National Institutes of Health Stroke Scale was done by an independent neurologist as part of the neurologic examination before and after the intervention and at discharge.

	Statistics. Comparisons of con-tinuous variables were made using the Mann-Whitney’s U test. P values

	< .05 were considered statistically significant. Exact 95% confidence intervals (CIs) were calculated for proportions.

	In all patients, the protection devices were used as intended, and all procedures were completed successfully. One patient, in whom the TRAP device was used, developed a major stroke within 2 hours of the intervention; another patient, in whom the NeuroShield device was used, had a transient ischemic attack 3.5 hours after the intervention.

	Before the intervention, MRI results were negative for all patients and showed hyperintensive foci after intervention for nine patients and 10 hemispheres (22.7%; 95%

	CI, 11.5%—37.8%). Three of these patients had bilateral disease (23.1%; 95% CI, 5.0%–53.8%), and six patients had unilateral disease (20.7%; 95% CI, 7.8%–39.7%). Positive MRI results were shown for three of

	13 patients with symptomatic lesions (23.1%; 95% CI, 5.0%—53.8%) and for seven of 31 patients with asymptomatic lesions (22.6%; 95% CI, 9.6%–41.1%).

	Patients with positive MRI results did not have a higher percent diameter stenosis (91% ± 7% for positive results versus 86% ± 10% for negative results) or a significantly different crossing profile of the filter devices (1.23 ± 0.11 mm for positive results versus 1.32 ± 0.17 mm for negative results) compared with patients with negative MRI results. The procedure duration and the amount of contrast agent used were also not significantly different.

	Eight of the nine patients who had positive MRI results did not experience any periprocedural neurologic complications. They had a small number of foci (median, 1; range, 1—3), with a mean size of 6.9 ¥ 2.7 mm2. The foci were located in the ipsilateral cerebral region in eight cases and in the contralateral circulation in one. In six of the nine cases with asymptomatic ischemic foci, follow-up MRI scans were obtained within a median of 4.2 months, with negative results in all cases.

	One patient had a major stroke. In this patient, 12 hyperintense foci were found on the postinterventional MRI scan, with the largest focus (covering an area of 84.5 mm2) observed of any of the patients with positive results on MRI. All foci in this patient were located in the contralateral hemisphere, and five foci were seen on follow-up MRI scans

	at 3.7 months, including the two largest foci. One patient experienced a transient ischemic attack (scotoma of the ipsilateral eye), which had no correlate on MRI scans.

	This study showed that focal ischemic lesions in the brain, as shown by diffusion-weighted MRI scanning, were found in 23% of patients who underwent neuroprotected carotid artery stenting. This in-cidence is similar to that reported in previous studies involving patients who underwent either cerebral angiography only3 or unprotected and protected carotid artery stenting preceded by cerebral angiography.1,2 In 90% of our patients, ischemic foci were not associated with periprocedural neurologic symptoms, and all asymptomatic lesions were reversible. Positive MRI results were independent of the presence of bilateral disease, symptomatic status of the patients, degree of the baseline stenosis, duration of the procedure, amount of contrast agent, and type of the protection device. Interestingly, focal ischemia was found, also in the contralateral cerebellum, in one of the asymptomatic patients in whom the MO.MA system was used.

	One patient in our series experienced a major stroke. Postinterventional MRI scans showed a significantly higher number of ischemic foci, which were also larger compared with the asymptomatic patients. The largest of these foci persisted on follow-up MRI. The foci were also exclusively found in the contralateral hemisphere in this patient.

	Our findings suggest that embolism was the underlying mechanism of cerebral ischemia. This is supported by analysis of the debris matter, which was collected or aspirated from carotid artery lesion sites.4,5 Several scenarios for embolism are conceivable. Before a protection system can be placed, guidewires, catheters, and sheaths must be manipulated within the aortic arch, which may result in the release of small particles of the often-calcified and atherosclerotic vessel wall. These particles would have had access to all supra-aortic vessels, which can result in ischemic lesions, including in the contralateral hemisphere, as was found in two of our patients.

	Particulate matter may also have passed through the filter, either through the pores, which have a size of between 80 and 150 µm, or along the vessel wall in the event the filter did not have complete wall apposition. The final steps of the procedure, filter retrieval and withdrawal of the device, may also have released small pieces into the cerebral circulation.

	Despite the use of cerebral protection devices, ischemic foci shown by diffusion-weighted MRI imaging were found in 23% of patients undergoing carotid artery stenting. Unavoidable interventional manipu-lation before the actual treatment of the target lesion may lead to serious neurologic complications. These findings show that interventionists should be extremely aware of adverse vessel anatomy and morphology. In addition, the medical device industry should concentrate not only on developing neuroprotective devices, but also on creating less injurious endoluminal equipment to be used for vessel access.

	Symptomatic neurologic complications seem to be only the tip of the iceberg. Further studies showing the clinical significance of “silent” ischemia of the brain, which may be associated with an impairment of cognitive function as has been shown with patients after cardiac surgery, need to be performed.6

Cerebral ischemia after carotid artery  stenting

	From the Division of Cardiovascular Diseases, Western Pennsylvania Hospital, Pittsburgh, Pennsylvania

	Americans older than 60 years of age represent the fastest growing segment of the population. The prevalence of hypertension increases with age, and elderly persons are particularly prone to the cardiovascular morbidity and mortality resulting from hypertension-associated conditions, including coronary artery disease, peripheral artery disease, stroke, renal disease, and heart failure. In the Third National Health and Nutrition Examination Survey (NHANES III), hypertension was present in 65.4% of the population aged 65 years and older.1 Other risk factors associated with increased rates of hypertension are increased body mass index and non-Hispanic African American race/ethnicity.2 Elderly African American women have the highest prevalence rates of hypertension in the general population.

	Isolated systolic hypertension, defined as systolic blood pressure of 140 mm Hg or above with a diastolic blood pressure of 90 mm Hg or below, is the most common form of hypertension in older Americans. It is present in approximately two thirds of hypertensive individuals older than 60 years of age.3 Diastolic blood pressure is a potent cardiovascular risk factor for patients younger than 50 years of age, but this changes for patients older than age 50, in whom systolic blood pressure plays a more important role. The results of several large epidemiologic studies indicate that increased systolic blood pressure is strongly associated with a greater risk of cardiovascular morbidity, stroke, and transient ischemic attacks. In the Multiple Risk Factor Intervention Trial (MRFIT), systolic blood pressure was a much stronger predictor of death due to coronary artery disease than diastolic blood pressure. The presence of isolated systolic hypertension doubles overall mortality and increases cardiovascular morbidity 2.5-fold. A recent clinical advisory statement issued by the National High Blood Pressure Education Program recommended that systolic blood pressure be made the major criterion for diagnosis, staging, and therapeutic management of hypertension for individuals older than 50 years of age.4

	In NHANES III, hypertensive patients older than age 60 had significantly lower rates of blood pressure control compared with younger individuals and non-Hispanic whites. In a study of elderly patients visiting their physicians for hypertension, approximately 40% had a blood pressure higher than 160/90 mm Hg, despite more than six visits per year to their physicians. Clinicians frequently achieve better success with controlling diastolic than systolic blood pressure,5 probably reflecting the misconception among many physicians that diastolic blood pressure control is more important than systolic blood pressure control in the elderly. As shown in table 1, there are substantial risks associated with undertreatment; for example, treated hypertensive men with a residual increase in systolic blood pressure of between 140 and 160 mm Hg exhibit a 68% increase in mortality compared with individuals who achieve a systolic goal blood pressure of below 140 mm Hg.6

	Several pathophysiologic features have been identified in the elderly hypertensive population, including increased sympathetic nervous system activity, overproduction of vasoconstrictors and salt-retaining hormones, chronic high-sodium dietary intake, and decreased renin secretion.7 Structural abnormalities of large conduit arteries as well as endothelial dysfunction from aging contribute to increased arterial stiffness and increased blood pressures. Aortic elasticity and distensibility decline with age, with an increased collagen-to-elastin ratio resulting from fragmentation of elastin and increased collagen deposition.8

	Increased central arterial stiffness leads to the increased systolic blood pressure and the wide pulse pressure seen in elderly hypertensive patients by causing the pulse wave velocity to increase. With each ejection of blood from the heart, a pulse wave travels from the heart to the peripheral vessels and is reflected at branching points back to the aorta and the left ventricle. In younger persons, a pulse wave velocity of approximately 5 m/sec is slow enough that the reflected wave reaches the aortic valve after closure, augmenting diastolic blood pressure and enhancing coronary perfusion. In the elderly hypertensive patient, an increased pulse wave velocity (eg, 20 m/sec) results in the reflective wave reaching the left ventricle before

	increased afterload, and decreased diastolic blood pressure. A widened pulse pressure is, in itself, a powerful independent predictor of cardiovascular end points in the elderly.9 The increased left ventricular systolic pressure, wall tension, and blood volume result in the left ventricular hypertrophy commonly seen in elderly hypertensive patients. This important structural change predisposes to the development of heart failure and increases the risk of myocardial infarction (MI), stroke, and sudden death.

	Hypertension is the most common risk factor for the develop-

	ment of congestive heart failure.10 Changes in myocardial diastolic function are regularly seen with

	the development of left ventricular hypertrophy. Myocardial contrac-tility is generally preserved, but diastolic dysfunction due to increased myocardial stiffness and impaired coronary flow reserve results in increased left ventricular filling pressures. These high pressures increase further with exercise and are reflected into the pulmonary capillaries. As a result, congestive heart failure with pulmonary congestion and dyspnea may develop. Data from the Framingham Heart Study indicate that a wide pulse pressure and increased systolic blood pressure confer a greater risk for the development of heart failure compared with diastolic blood pressure.11 Although most of the mortality from heart failure occurs in patients with a significant degree of systolic dysfunction (ejection fraction below 40%), morbidity is high for patients with diastolic dysfunction, and approximately 40% of clinical episodes requiring hospitalization occur in patients with normal or near-normal left ventricular systolic function. The pathogenesis of hypertension in elderly patients is summarized in table 2.

	Clinical trials on the therapy for hypertension

	Nonpharmacologic treatment of hypertension remains a useful therapeutic adjunct for all patients, including the elderly. The Trial of Nonpharmacological Interventions in the Elderly (TONE) showed that reduced sodium intake, weight loss, or both, were safe, effective, and feasible in elderly, obese patients with mild hypertension.12

	Several placebo-controlled trials have shown that treatment of elderly patients with increased systolic, diastolic, or both systolic and dia-stolic blood pressure greatly reduces cardiovascular morbidity and mortality. The Systolic Hypertension in the Elderly Program (SHEP) study showed the benefit of treating isolated systolic hypertension in older adults. In this study, 4,736 patients older than 60 years of age, with a systolic blood pressure above 160 mm Hg and a diastolic blood pressure below 90 mm Hg, were randomly assigned to receive placebo or antihypertensive stepped-care drug treatment with low-dose chlorthalidone and atenolol. The 5-year incidence of total stroke was 5.2 per 100 participants receiving treatment and 8.2 per 100 participants receiving placebo, a statistically significant reduction of 36%. After a mean of 4.5 years, the incidence of left ventricular failure was reduced by 54% in the diuretic-based therapy group.13 Chlorthalidone-based treatment also had favorable effects on the hypertrophied myocardium, reducing left ventricular mass by 13% over 3 years.14 There also was a trend toward lower depression and dementia scores with diuretic-based therapy.

	Angiotensin-converting enzyme (ACE) inhibitors (lisinopril or enalapril), as well as calcium antagonists (isradipine or felodipine), were noted to have efficacy similar to conventional treatment with diuretics or beta blocking agents in elderly patients with hypertension. In the Swedish Trial in Old Patients with Hypertension-2 (STOP-2), 6,614 patients with hypertension (blood pressure ≥ 180/105 mm Hg), aged 70 to 84 years, were followed up for 5 years.15 They were randomly assigned to receive one of three treatments: conventional agents (diuretics, beta blocking agents), ACE inhibitors, or calcium antagonists. The blood pressure—lowering effects were similar for all groups. The total mortality was not significantly different among the groups, but ACE inhibitors were associated with significantly fewer MIs and less congestive heart failure compared with calcium antagonists.

	Long-acting nifedipine also decreased the number of strokes and arrhythmias in elderly hypertensive patients, as shown in the Shanghai Trial of Nifedipine in the Elderly (STONE), which included 1,632 patients randomly assigned to receive placebo or twice-daily dosing of slow-release nifedipine.16 The Sys-

	tolic Hypertension in Elderly in Europe (Syst-Eur) trial also showed the benefit of calcium antagonist—

	based therapy (nitrendipine) in reducing cardiovascular and cerebrovascular events in patients older than 60 years of age with isolated systolic hypertension.17 Nitrendipine with added enalapril and hydrochlorothiazide as required reduced systolic blood pressure by 23 mm Hg and diastolic blood pressure by

	7 mm Hg after 2 years of follow-up. There was a 42% reduction in stroke rate and a 26% reduction in cardiac end points, including heart failure, fatal and nonfatal MI, and sudden death. The benefits of antihypertensive therapy were seen despite a target blood pressure that was higher than current recommendations.

	The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) consisted of 42,418 patients with hypertension aged 55 years or older, with at least one other coronary artery disease risk factor. Patients received chlorthalidone, amlodipine, lisinopril, or doxazosin as first-line therapy.18 Doxazosin treatment was associated with a higher risk of cardiac events, particularly heart failure, and was dropped midway through the study. The final results showed that chlorthalidone, amlodipine, and lisinopril were equally effective in preventing fatal coronary artery

	no difference in overall mortality among the three treatment groups. The results were consistent for all major prespecified subgroups, including patients older than 65 years. Higher rates of stroke in the ACE inhibitor group in ALLHAT were the result of an increased incidence of stroke in the large African American subgroup, whose blood pressures were less well controlled. This finding was not seen in non-African American subjects, suggesting that the effect was related to the difference in blood pressure rather than to an intrinsic inferiority of the ACE inhibitor. Chlorthalidone was superior in preventing heart failure compared with either amlodipine or lisinopril. The diuretic-based regimen reduced occurrence of heart failure by 22% compared with an amlodipine-based treatment program. Patients randomly assigned to receive chlorthalidone achieved a statistically significant lower systolic blood pressure (by 3 mm Hg) than the lisinopril group, probably because of protocol-derived constraints in the selection of add-on medications. About two thirds of the elderly patients achieved a goal blood pressure below 140/90 mm Hg with the use of an average of two antihypertensive drugs per patient. Given current recommendations for lower blood pressure targets (< 130/80 mm Hg) in patients with diabetes (who constituted 36% of the ALLHAT population), it is likely that more than one drug would be required to meet blood pressure goals in approximately 80% of the ALLHAT cohort.

	The benefits of angiotensin-receptor blockade in elderly patients with isolated systolic hypertension were shown in the Losartan Intervention for Endpoint Reduction (LIFE) substudy.19 In that trial, 1,326 patients (mean age, 70 years) with isolated systolic hypertension were randomly assigned to receive losartan or atenolol with hydrochloro-

	thiazide as add-on therapy, followed by additional agents as needed. Despite a similar decrease in blood pressure of 28/9 mm Hg, there was a 25% reduction in the combined primary end point of cardiovascular mortality, stroke, and MI in patients assigned to losartan. Significantly more electrocardiographic left ventricular hypertrophy regression occurred with losartan treatment, and there was a striking 40% reduction in nonfatal and fatal stroke, a 38% reduction in new-onset diabetes, and a 38% reduction in total mortality compared with atenolol.

	The relatively poor performance of atenolol in the LIFE isolated systolic hypertension substudy raises questions regarding the suitability of beta blocking agents as first-line therapy for hypertension in elderly patients. In a previous meta-analysis of 10 hypertension trials, Messerli and colleagues examined data derived from over 16,000 patients randomly assigned to receive diuretics or beta blocking agents, or both.20 According to this analysis, two thirds of patients on diuretic monotherapy were well controlled compared with only a third of those receiving beta blocking agents. Furthermore, diuretic therapy was found to be superior in preventing strokes, coronary artery disease, cardiovascular mortality, and all-cause mortality.20 It should be emphasized, however, that beta blocking agents remain the preferred agents in patients with coronary artery disease, who constitute a significant fraction of the elderly hypertensive population. Table 3 lists treatment recommendations for patients with isolated systolic hypertension. The figure shows the pooled analysis of the outcome of eight trials of older patients with isolated systolic hypertension.21

	The exciting concept of secondary stroke prevention with antihypertensive therapy was shown in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). In that study, 6,105 patients (mean age, 64 years) with a history of stroke or transient ischemic attack were randomly assigned to receive placebo or the ACE inhibitor perindopril (with the addition of indapamide at the discretion of the investigator). Blood pressure was reduced by 9/4 mm Hg in patients receiving perindopril alone and 12/5 mm Hg in those receiving both perindopril and indapamide. There was a 28% relative risk reduction in stroke in the active treatment group. The reduction in stroke risk did not depend on baseline blood pressure and was comparable in magnitude for hypertensive and nonhypertensive patients.22 Because the study de-

	sign made it difficult to determine whether the ACE inhibitor or the diuretic was responsible for the beneficial effects, combination treatment is recommended for patients who have had a stroke.

	Special issues with antihypertensive therapy for elderly patients According to recommendations of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), antihypertensive therapy is indicated for all elderly patients with systolic blood pressure above 140 mm Hg or diastolic pressure above 90 mm Hg. For patients with diabetes mellitus or renal impairment, a lower threshold for treatment of 130/80 mm Hg is indicated. The benefits of treatment are clearly established, yet surveys indicate that fewer than 25% of patients are at or below goal blood pressure. Clinical inertia is a hindrance to optimizing blood pressure control. Physicians are encouraged to titrate medications upward, combine different agents, and reinforce lifestyle modifications when the systolic or diastolic blood pressure is not at goal. Medical regimens should be tailored to the patient’s coexisting conditions. Certain comorbid illnesses are compelling reasons for the selection of particular agents, as shown in table 4.

	Particular attention should be paid to the technique of blood pressure measurement in the elderly. A falsely increased brachial cuff blood pressure reading may be caused by diffuse arteriosclerosis and increased arterial stiffness, a phenomenon referred to as pseudohypertension. In these patients, measurement of blood pressure with automated devices that use oscillometric techniques will give more accurate readings. Postural hypotension despite antihypertensive therapy, treatment-resistant hypertension, and the absence of target organ damage in patients with long-standing “hypertension” are some of the clinical features suggestive of pseudohypertension.23

	Central sympatholytic agents and reserpine should generally be avoided in elderly patients because they may adversely affect cognition. In general, drugs should be initiated at a low dose and titrated gradually to effect a slow reduction in increased blood pressure. Special attention should be paid to renal function because the dose may need to be adjusted for certain medications. Low-dose diuretic therapy is well tolerated. Nonsteroidal anti-inflammatory drugs are commonly used by the elderly and may contribute to difficult blood pressure control. These agents cause sodium retention and may adversely affect renal function. The use of fixed-drug combinations is an attractive option to reduce the number of pills a patient must take and therefore improve medication compliance.

	The recommendations in JNC 7 state that all hypertensive patients older than 50 years of age should have lying and standing blood pressure recordings periodically. Readings in the sitting position may miss the diagnosis of orthostatic hypo-tension (a supine-to-standing blood pressure reduction of > 20 mm Hg systolic or > 10 mm Hg diastolic). Diabetic patients, patients taking diuretics or vasodilators, and patients with isolated systolic hypertension are particularly prone to this condition. Volume depletion, baroreflex dysfunction, and autonomic insufficiency may contribute to

	the development of this difficult condition in elderly patients. Alpha blocking agents (doxazosin, terazosin) and direct-acting vasodilators (minoxidil, hydralazine) should be avoided or used with caution because they may cause or exacerbate orthostatic hypotension.

	Hypertension is a major risk factor for the development of cardiovascular, cerebrovascular, and renal events in elderly patients. Because the baseline risk of cardiovascular events is so much higher in these patients, aggressive lowering of blood pressure reaps a much greater reduction in complications in this subgroup compared with the hypertensive population as a whole. The importance of treating isolated systolic hypertension cannot be overemphasized. Pharmacologic therapy, with an emphasis on low-dose diuretics, angiotensin-receptor blockers, ACE inhibitors, and calcium channel blocking agents should be initiated whenever the systolic blood pressure exceeds 140 mm Hg. An aggressive stance with African American patients should be adopted because this subgroup shows a higher risk of cerebrovascular and cardiovascular complications. Clinical inertia should be avoided, and active pursuit of a treatment goal of less than 140 mm Hg systolic blood pressure is imperative. Combination therapy with two or more antihypertensive agents will be needed to achieve this target in the majority of patients, and many will require three or more drugs. Heart failure, type 2 diabetes mellitus, chronic renal failure, previous stroke, and MI are frequent comorbid conditions in the elderly that warrant an individualized approach to blood pressure control and mandate the inclusion of specific drug agents in the therapeutic regimen. The presence of underlying endocrine disorders and renovascular disease may pose a therapeutic challenge, and early referral to a hypertension specialist is encouraged if goal blood pressure cannot be achieved with three medications.  n

Hypertension  in older patients

	Before phosphodiesterase-5 (PDE-5) inhibitors were developed, treatment of erectile dysfunction (ED) was difficult and remained in the realm of the urologist. The approval of the first effective oral agent for the treatment of ED in 1998 focused the attention of the medical profession on the magnitude of the problem of ED and its effect on the quality of life of affected patients. Because patients are reluctant to broach the subject, physicians who can now offer effective treatment should.

	In his overview, Dr. Kloner (page 35) summarizes the evidence that ED is related to endothelial dysfunction in most patients. Endothelial dysfunction is also known to be an early stage in the development of arterial and arteriolar disease, including coronary artery disease (CAD), carotid and cerebrovascular disease, peripheral vascular disease, and hypertension. We have also known for some time that the risk factors that are associated with an increased prevalence and incidence of CAD act by injuring the endothelium. It is not surprising, therefore, that the same risk factors are involved in the endothelial damage that results in ED, making it an early form of arterial disease, as the study by Kaiser and colleagues1 showed. Another study indicating that these risk factors presage ED was reported by Fung and colleagues.2 They evaluated a population of men for the presence of risk factors for CAD from 1972 to 1974. In 1998 they found that the patients who had risk factors 25 years before had an increased prevalence of ED compared with those without risk factors. It seems probable that controlling the risk factors before ED becomes clinically evident might prevent the development of ED, and possibly other arterial diseases. There is no strong evidence, however, that the disease is reversible with the control of risk factors once the arterial disease, either ED or other forms, is present.

	Penile erection depends on smooth muscle relaxation in penile arterioles and cavernosal lacunae. Smooth muscle relaxation occurs because nitric oxide released by the 3,5¢-cyclic guanosine monophosphate (cGMP) and through a cascade of actions, removes calcium from the contractile elements of the smooth muscle. Because sildenafil, vardenafil, and tadalafil all work by inhibiting the PDE-5 enzyme and thus preventing the breakdown of cGMP, any contribution of organic nitrates that can be bioconverted into nitric oxide can significantly increase cGMP and prolong or magnify smooth muscle relaxation and vasodilatation. In some individuals this can result in a marked drop in blood pressure, which is the basis for the contraindication for use of organic nitrates in patients taking PDE-5 inhibitors.

	PDE-5 inhibitors in normal individuals cause smooth muscle relaxation, vasodilatation, and a slight, clinically insignificant decrease in systolic and diastolic blood pressure. The vasodilatation and smooth muscle relaxation are the cause

	of most of the side effects of the drugs: headache, nasal stuffiness, and esophageal reflux. Dr. Kloner notes that clinically important vasodilatation occurs in such diseases as primary and secondary pulmonary hypertension, where more marked and selective drops in pulmonary vascular resistance and pulmonary artery pressure occur compared with systemic vascular resistance and systemic arterial pressure. This is probably related to upregulation of PDE-5 in the pulmonary circulation in patients with those diseases. It is hoped the PDE-5 inhibitors will be therapeutically useful in this disease.

	Most of the cautions mentioned in the ACC/AHA Expert Consensus Guidelines in 19993 were the result of the exclusions from the randomized, placebo-controlled trials of sildenafil available at that time. Since then there have been extensive reports on the safety and effectiveness of sildenafil and, with lesser experience, of vardenafil and tadalafil, in the general male population with ED, as well as in more specific populations (eg, patients with CAD, hypertension, diabetes, and congestive heart failure).

	Because certain antihypertensive and antidepressant drugs can cause ED, one approach would be to discontinue or substitute other drugs to see if the ED improves. However, if the drugs are effective and have no other adverse effects, a better approach would be to see if the ED responds to a PDE-5 inhibitor and continue the effective drug. Dr. Kloner discusses the relative and absolute contraindications to the use of PDE-5 inhibitors with some cautions: alpha-adrenergic blockers, drugs used in both hypertension and, more importantly in the age group of interest, in benign prostatic hyperplasia. Although the studies showing a marked drop in blood pressure in some patients with

	are small, the Food and Drug Administration recommendations are those that the medical profession must follow.

	The double-blind, placebo-controlled trials, the experience with the open-label studies, and the prescription-monitoring studies are all convincing that total death, acute myocardial infarction, and stroke are no more frequent in patients taking PDE-5 inhibitors than in those not taking them. There is a small risk of acute myocardial infarction occurring within 2 hours of sexual activity, however, which is probably related to the increase in physical activity and myocardial oxygen demand. For the majority of men, the increase in metabolic equivalents (METs—where 1 MET is the VO2 uptake at rest) is 3 to 5 METs, a modest increase in VO2. The Princeton Conference4 referred to by Dr. Kloner categorized patients with cardiovascular disease into low-, intermediate-, and high-risk groups. Those with high risk must have their cardiovascular disease evaluated and controlled before engaging in the physical activity associated with sexual intercourse. The low-risk group can have their ED treated without further cardiovascular workup, whereas the intermediate-risk patients should have their capacity to exercise to the extent demanded by sexual activity evaluated before being treated for their ED. This algorithm will be further modified as a result of a conference held in June 2004. The physician should remember that the increase in myocardial oxygen demand occurs in the partner as well as the patient with ED, and their risk of increased sexual activity should be considered.

	ED is an arterial disease and should stimulate examination of the patient for other, more serious, unsuspected arterial disease. Conversely, patients with clinical coronary artery and other arterial diseases should be questioned about possible ED, since the successful treatment of ED can, in some patients, markedly improve their quality of life.

Erectile dysfunction Another  manifestation of arterial disease Melvin D. Cheitlin, MD

	From the Heart Institute, Good Samaritan Hospital, and the Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California, Los Angeles

	Erectile dysfunction and risk factors If a patient went to see his health care worker some 15 years ago about the problem of impotence (now referred to as erectile dysfunction [ED]), in many cases, he may have been told that it was primarily a psychological problem. Indeed, psychogenic difficulties, such as anxiety, depression, and problems in relationships, may contribute to ED. In men older than 40 to 50 years, however, the etiology is more likely to be organic in nature. Common organic causes include vascular (endothelial dysfunction, frank atherosclerosis), neurogenic (cerebrovascular event, spinal cord injury, multiple sclerosis, neuropathy), or endocrine (diabetes [which also includes elements of vascular and neurogenic ED], hyperthyroidism, hypothyroidism, hyperprolactinemia), trauma, structural abnormalities (such as Peyronie’s disease), or causes related to such drugs as thiazide diuretics, beta blocking agents, centrally acting antihypertensive medicines, selective serotonin reuptake inhibitor—type antidepressants, alcohol, nicotine, and others.1

	Because an erection is a vascular event involving vasodilation of vascular structures in the corpus cavernosum of the penis, endothelial function must be intact. Factors that injure the endothelium and lead to endothelial dysfunction may contribute to ED. Thus, hypertension, diabetes, smoking, lipid abnormalities (especially low high-density lipoprotein [HDL] cholesterol and high total cholesterol), lack of physical activity, and obesity, which are known risk factors for coronary artery disease (CAD), are also risk factors for ED.2,3 Therefore, patients with these risk factors should be questioned about their sexual health. Conversely, patients who present with ED should be questioned about cardiovascular risk factors. A recent study found that men who presented with ED were more likely to have endothelial dysfunction.4 Furthermore, they were more likely to have cardiovascular risk factors and an exercise stress test that was positive for ischemia.5 Pritzker coined the term penile stress test to make the point that ED may be an early warning that a man may have vascular disease.5

	How common is ED once vascular disease occurs? In a recent study, my colleagues and I queried men with stable angina pectoris about their sexual health with a five-question survey called the Sexual Health Inventory for Men.6 This questionnaire focused on two key issues—the ability to attain an erection and the ability to maintain an erection through successful completion of intercourse. Answers to questions were scored from 0 to 5 and then added. Scores of 21 or less suggested ED. Of the 76 men, 75% had ED according to their questionnaires, and ED was severe in 25% of these men. Therefore, ED is common in the CAD patient.

	ED is also common in patients with diabetes. In one study, the prevalence of ED was greater than 75% in diabetic men older than 60 years.7 Diabetes can induce ED both by accelerating vascular disease and via a diabetic neuropathy. Loss of sensation on the neurologic examination correlated with the development of ED in diabetic men. The incidence

	of ED is also high in patients with hypertension.8

	Age, of course, is another factor associated with ED. In the Massachusetts Male Aging Study (MMAS), 52% of men between the ages of 40 and 70 years had some degree of ED.2 At age 40, 5% had complete ED, meaning they were never able to achieve an erection satisfactory for sexual activity. By age 70, 15% had complete ED. Moderate degrees of ED also increased with age, whereas mild ED did not appear to be affected by age. After correction for age, heart disease, hypertension, diabetes, and low HDL cholesterol correlated closest with development of ED. In a follow-up study of MMAS, smoking and passive exposure to smoke also predicted ED.9

	Unfortunately, there is a paucity of data that examine whether control of these cardiovascular risk factors will reverse ED.10 Some, but not all, studies suggest that smoking

	cessation will help. Unfortunately, even passive smoking may worsen ED.9 HMG-CoA reductase inhibitors  (statins) were shown to improve spontaneous nocturnal erections in another analysis.11 There is a lack of data on whether tight control of hypertension or diabetes will help. One study suggested that better control of some risk factors may improve response to oral therapy with sildenafil.12

	Oral pharmacologic therapy for ED in the form of the phosphodiesterase-5 (PDE-5) inhibitors is effective not only in a general population, but also in men with ED who have vascular disease, including ischemic heart disease13 and hypertension.14 The PDE-5 inhibitor sildenafil improved ED in 72% of men with chronic ischemic heart disease and in about the same percentage

	of men with hypertension, most of whom were on antihypertensive medicines. In a general population of men with ED, sildenafil improved ED in 82% at the 100-mg dose. Efficacy rates were somewhat lower in men with diabetes. Vardenafil and tadalafil also have been shown to be effective in men with ED, including those with ED of a vascular basis. Their efficacy in diabetic men also tends to be somewhat lower than their efficacy in nondiabetic men.15

	PDE-5 inhibitors prevent the breakdown of cyclic guanosine monophosphate, the substance that ultimately causes smooth muscle cell relaxation in the vasculature of the corpus cavernosum of the penis. Because the enzyme PDE-5 is present not only in the vasculature of the penis, but also in systemic arteries and veins, PDE-5 inhibitors are mild vasodilators. Because they dilate ar-teries and veins, they are associated with small reductions in arterial pressure. In general, these small reductions are not considered clinically significant. The vasodilator effect can account for some of the nuisance adverse effects of these agents, including flushing, headache, and nasal stuffiness.15

	The PDE-5 inhibitors are not aphrodisiacs. Patients must be instructed that sexual stimulation is needed for these agents to be effective. Sildenafil and vardenafil have

	4 hours, whereas tadalafil has a long half-life of 17.5 hours. Sildenafil and vardenafil have some interaction with food, and fatty meals may delay the onset of their action. Tadalafil does not have a food interaction.

	All three PDE-5 inhibitors are contraindicated in patients taking organic nitrates, including all nitroglycerin preparations and long-acting nitrates, such as isosorbide mononitrate and isosorbide dinitrate.16 It is important for cardiologists to realize that the contraindication holds for patients taking intermittent nitrates, such as sublingual nitroglycerin tablets or sprays, as well as regularly dosed nitrates. In general, the PDE-5 inhibitors are safe to use in patients taking the usual antihypertensive agents in whom they are associated with no or small additive decreases in blood pressure.

	In general, the PDE-5 inhibitors are safe to use in patients taking the usual antihypertensive agents in whom they are associated with no or small additive decreases in blood pressure. In general, the adverse effect profile of the PDE-5 inhibitors is not worsened when patients take antihypertensive medicines—even in those taking multiple antihypertensive agents. Alpha blocking agents, however, appear to be an exception. A 25-mg dose of sildenafil may be administered with alpha blockers at any time, but it is recommended that doses of 50 or 100 mg not be administered within a 4-hour window of alpha blocker therapy because some patients have developed orthostatic hypotension when given more than 25 mg sildenafil simultaneously with doxazosin. Vardenafil is absolutely contraindicated with alpha blockers, as some patients taking

	terazosin or tamsulosin have developed orthostatic hypotension when taking this combination. Tadalafil is contraindicated with alpha blockers, except for a 0.4-mg dose of tamsulosin, because some patients who received tadalafil plus doxazosin developed orthostatic hypotension. Vardenafil carries a warning that it should not be given to patients with congenital QT prolongation or patients taking type 1A antiarrhythmics, such as quinidine or procainamide, or type 3 antiarrhythmics, such as sotalol or amiodarone. Neither sildenafil nor tadalafil carries a QT interval warning. The PDE-5 inhibitors have not been associated with documented cases of torsades de pointes. In addition, studies assessing rates of myocardial infarction (MI) or death did not suggest an increase in these events in men taking PDE-5 inhibitors as part of double-blind, placebo-controlled, or open-label studies.16 In postmarketing surveillance studies of sildenafil, there was no evidence of an increase in MI or death compared with what would be expected in an age-matched population.17,18 Similar postmarketing surveillance data on vardenafil and tadalafil are not yet available.

	In general, the PDE-5 inhibitors are safe in most stable cardiac patients. They do not exacerbate ischemia when given to patients with CAD undergoing exercise testing; however, treatment for sexual dysfunction in unstable cardiac patients, in general, should be withheld until their cardiac condition is stabilized and should be approached as outlined in the Princeton consensus document.19 Furthermore, any vasodilators, including PDE-5 inhibitors, should be used with great caution in patients who could deteriorate hemodynamically as a result of vasodilator therapy, such as those with left ventricular outflow obstruction or aortic stenosis, hypotensive patients, and patients with congestive heart failure with low blood volume. Additional guidelines regarding the safety of sildenafil and the cardiac patient were issued by the Ameri-can College of Cardiology and the American Heart Association.20

	Investigational studies are exploring the potential cardiac applications of PDE-5 inhibitors.21 In many studies, sildenafil was shown to reduce pulmonary artery pressure and pulmonary vascular resistance in patients with primary and secondary pulmonary hypertension. It was also shown to improve endothelial function measured by flow-mediated vasodilation of the brachial artery in patients with endothelial dysfunction associated with congestive heart failure or diabetes. Early studies suggest that sildenafil may improve hemodynamics and exercise tolerance in patients with congestive heart failure. These agents may be explored as possible adjunctive therapies for patients with hypertension.  n

Erectile dysfunction The cardiovascular  connection

	More than one in five patients older than 50 years with type 2 diabetes who have no symptoms of coronary artery disease (CAD) had silent myocardial ischemia on stress myocardial perfusion imaging, according to authors of the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study. Furthermore, traditional cardiac risk factors were not associated with abnormal stress tests.

	According to the authors, led by Frans J.Th. Wackers, MD, professor and director, cardiovascular nuclear imaging and exercise laboratories, Yale University, New Haven, Conn., “…this study indicates that totally asymptomatic patients with diabetes have at least an intermediate probability of CAD, a prevalence that may justify screening by noninvasive testing such as stress myocardial perfusion imaging.”

	As reported in Diabetes Care (2004;27[8]:1954-1961), the DIAD study was designed to assess the prevalence and clinical predictors of silent myocardial ischemia in asymptomatic patients with type 2 diabetes using adenosine-stress single-photon emission-computed tomography (SPECT) myocardial perfusion imaging. All patients were recruited from diabetes and primary care outpatient practices. For this analysis, 522 patients aged 50 to 75 years with type 2 diabetes in whom angina was ruled out by questionnaire underwent SPECT imaging. Patients were under reasonable metabolic control (mean A1c = 7.1%) at entry. Fifteen percent of the study group was African American, a group that was lacking in prior screening studies, note the authors.

	Overall, 113 patients (22%) of the cohort had abnormal SPECT studies, including regional perfusion abnormalities in 16% and markedly abnormal perfusion images with moderate or large stress defects in 6%. In addition, 6% had normal myocardial perfusion but had other significant test abnormalities, such as transient ST-segment depression, left ventricular dysfunction, or transient ischemic left ventricular dilation.

	The strongest predictor of an abnormal stress test was a diminished heart rate response to the Valsalva maneuver. Moderate or large perfusion abnormalities were strongly associated with a decreased Valsalva response, male sex, and symptoms of autonomic neuropathy. Traditional cardiac risk factors or inflammatory or prothrombotic markers were not predictive of silent ischemia or perfusion abnormalities.

	The authors note that the American Diabetes Association (ADA) recommends screening (by stress testing) of patients with two or more CAD risk factors, but in this study, “markedly abnormal myocardial perfusion results occurred with

	equal frequency among patients with two or more and less than two risk factors.” Selecting only those patients for screening who had met ADA guidelines would have failed to identify 41% of the patients with silent ischemia.

	They add that cardiac autonomic function testing “may have an important role in the CAD risk assessment of patients with type 2 diabetes because of the important association shown in this study.”

Silent ischemia is common in asymptomatic patients with type 2 diabetes

	Almost one third of older patients with heart failure for whom angiotensin-converting enzyme (ACE) inhibitors are appropriate do not receive them, according to a recent analysis of a Medicare database.

	Some, but not all, of the ACE inhibitor underutilization in this population can be explained by the use of angiotensin receptor blockers (ARBs) as a therapeutic substitute for ACE inhibitors for the treatment of heart failure, according to principal investigator Frederick A. Masoudi, MD (Circulation. 2004;110[6]:724-731).

	As part of the Centers for Medicare and Medicaid Services’ National Heart Care Project, he and colleagues reviewed the records of 17,456 Medicare patients with heart failure and left ventricular systolic dysfunction. The review covered two time periods: April 1998 to March 1999 and July 2000 to June 2001. All patients included were at least 65 years old (mean age: 78 years) and none had contraindications to treatment with an ACE inhibitor.

	They found that prescription rates for ACE inhibitors did not increase from study period one to study period two. Overall, 32% of the study participants were prescribed an ACE inhibitor at discharge. The proportion of patients treated with ACE inhibitors was 69% from 1998 to 1999 and 67% between 2000 and 2001. Prescription of an ACE inhibitor at discharge was associated with a 14% relative reduction in 1-year mortality.

	ARBs were prescribed at discharge to 10% of patients. When ACE inhibitors and ARBs were considered together, 78% of patients had prescriptions at hospital discharge. Discharge prescription of either ACE inhibitors or ARBs was associated with a 17% relative reduction in mortality.

	“The underuse of life-saving medications in patients with systolic heart failure is a pervasive problem throughout the health care community,” said Dr. Masoudi, assistant professor of medicine, Denver Health Center and the University of Colorado Health Sciences Center in Denver.  “Our study provides good evidence ... to validate current guideline recommendations that all patients with systolic dysfunction should be getting ACE inhibitors, unless they have a contraindication to the use of these drugs.”

	The use of ACE inhibitors in women, the very old, African Americans, and patients with kidney disease and other high-risk conditions has been controversial because these populations have been underrepresented in clinical trials of ACE inhibitor therapy. The clinical benefit of ACE inhibitors in this study was therefore reassuring, according to Dr. Masoudi.

	Patients who had more severe kidney disease as defined by higher levels of creatinine were signifi-cantly less likely to receive ACE

	inhibitors. “The patterns of ACE inhibitor use in the present study suggest the possibility of therapeutic nihilism in patients with renal insufficiency, whereas the mortality analyses indicate that older patients and those with renal insufficiency may have the most to gain from treatment,” the authors write.

	In an editorial that accompanies the study, Mark Hlatky, MD, notes that despite a class I recommendation for the use of ACE inhibitors as treatment for heart failure by the American College of Cardiology/American Heart Association Guidelines Committee, the use of ACE inhibitors for this indication has reached a plateau, leaving “a stubborn, persistent gap between ideal practice and the actual use of ACE inhibitors for heart failure.” Closing this gap may require active interventions, such as reminder systems, chart-based or computerized approaches, and critical care pathways within hospitals, according to Dr. Hlatky, professor of medicine and professor of health research and policy at Stanford University, Calif. Multidisciplinary approaches are particularly attractive, he writes, because the care of patients with heart failure requires management of multiple factors, including adherence to diet and medication recommendations.

ACE inhibitors underprescribed in older heart failure patients

	In the first study to examine whether fish intake can affect atrial fibrillation (AF), eating tuna or other broiled or baked fish, but not fried fish or fish sandwiches, was found to lower the incidence of AF among older adults. The study was also the first to focus on the effects of the types of fish meals eaten, said lead author Dariush Mozaffarian, MD, MPH. The results were published in Circulation (2004;110[4]:368-373).

	“The results suggest that regular intake of tuna or other broiled or baked fish may be a simple and important deterrent to AF among older men and women,” said Dr. Mozaffarian, instructor of medicine and researcher in the Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School

	Using the database from the National Heart, Lung, and Blood Institute’s Cardiovascular Health Study, a prospective, population-based, multicenter study of 4,815 people aged 65 years or older who were enrolled in 1989 and 1990, the authors identified 980 cases of diagnosed AF over 12 years of follow-up. Participants had their dietary intake assessed at baseline through a questionnaire.

	The incidence of AF was 19 per 1,000 person-years among persons who consumed tuna or other fish at least five times per week, compared with 33 per 1,000 person-years among those who consumed it less than one time per month (P < .0001).

	After adjustment for potential confounders, persons who reported eating those fish one to four times per week had a 28% lower risk of AF, and those who had five or more servings had a 31% lower risk compared with those who ate fish less than once a month. Fried fish or fish sandwich consumption was not associated with a lower risk of AF.

	An earlier study of a subgroup of the same population found that eating tuna or other broiled and baked fish correlated with increased biomarkers of long-chain n-3 fatty acids (omega-3 fatty acids) in the blood. No such association was found for fried fish/fish sandwiches, which suggests that these fish meals were either mostly lean (white) fish or that the preparation method affected the n-3 fatty acid content, according to Dr. Mozaffarian. Most fried fish or fish sandwiches eaten in the United States are lean (white) fish such as cod and pollock, he noted.

	Further research is needed to evaluate the relationship between n-3 fatty acid supplements and risk of AF, he told Cardiology Review.

	The American Heart Association’s dietary guidelines recommend that healthy adults eat at least two servings of fish per week, particularly fish such as mackerel, lake trout, herring, sardines, albacore tuna, and salmon.

	In another study in Circulation (2004;110:1042-1046), researchers found that at age 40, the average lifetime risk for AF is 26% for men and 23% for women. “In other words, about one in four would develop AF before they die,” said Donald M. Lloyd-Jones, MD, ScM, assistant professor of medicine and preventive medicine at the Feinberg School of Medicine at Northwestern University, Chicago.

	He and colleagues reviewed data from the Framingham Heart Study, in which 3,999 men and 4,726 women had documented examinations, medical histories, and electrocardiograms from 1968 to 1999. During the study, 936 participants developed AF and 2,621 died without prior AF. At age 80, the lifetime risk for AF did not change substantially despite fewer remaining years of life. The risk was 22.7% for men and 21.6% for women at age 80.

Broiled or baked fish lowers risk of AF in older adults

	September has come to represent a truly special time at Cardiology Review, the month in which we publish our annual issue devoted to cardiovascular disease in the elderly. This year we present three continuing medical education (CME) articles (with accompanying commentaries) that revisit two subjects always of interest

	to our readers (hypertension and polypharmacy) and introduce one subject that has received enormous attention of late (erectile dysfunction).

	Treatment options for hypertension in the elderly are a continuing concern for physicians for a variety of reasons, not the least of which is the increasing number of people with high blood pressure living until their seventies, eighties, and even nineties. Drs. Harun Otieno and Alan H. Gradman have provided a comprehensive overview of not only the treatment issues but also the epidemiology and pathology of hypertension in the elderly. As Dr. Pantel S. Vokonas notes in his commentary, isolated systolic hypertension has emerged as a dominant risk factor for adverse cardiovascular outcomes in this age group.

	Unfortunately, the use of a variety of drugs (which is often what hypertensive patients require, as per JNC 7 guidelines) can also lead to abuse. Hence, the importance of our second article: managing polypharmacy issues in the elderly. Patients in this age group have to be especially careful about drugs that have troubling side effects, drugs that may interact with one another, and drugs that have inherent compliance problems, eg, those requiring multiple doses per day. Drs. C. Wayne Weart and Nannette M. Berensen update their previous contribution to this debate in a new and highly informative presentation. Along with the pertinent commentary by Dr. Stephen P. Glasser, I think our readers will find the polypharmacy discussion very helpful.

	Our third topic, erectile dysfunction, is a new one for our readers. Always a problem with diabetic patients, physicians now encounter it in other patients as well, especially elderly ones. Its relation to cardiovascular disease (especially endothelial dysfunction) and pharmacologic therapy is reviewed by Dr. Robert A. Kloner, an expert in the field and one of the leading researchers of therapy with PDE-5 inhibitors. The commentary provided by Dr. Melvin D. Cheitlin emphasizes what can be done about this problem and points out the risks associated with drug therapy in coronary patients.

	In a bonus feature in the stroke section, Drs. Joachim Schofer and Thilo Tübler from Germany assess the problem of focal cerebral ischemia after neuroprotected carotid artery stenting. Of the 42 patients studied, about 25% had predominantly silent cerebral ischemia despite the neuroprotection. The safety concerns of the authors are echoed by Dr. John J. Ricotta, our vascular surgery consultant, in his commentary.

September 2004

Polypharmacy%u2014the good, the bad, and the ugly

Managing polypharmacy issues

Hypertension in the elderly: Ubiquitous but not innocuous Pantel S. Vokonas, MD

Carotid artery stents: Benefits and challenges John J. Ricotta, MD

Case report: Carotid artery stenting in a 73-year-old man

Cerebral ischemia after carotid artery stenting

Hypertension in older patients

Erectile dysfunction Another manifestation of arterial disease Melvin D. Cheitlin, MD

Erectile dysfunction The cardiovascular connection

Silent ischemia is common in asymptomatic patients with type 2 diabetes

ACE inhibitors underprescribed in older heart failure patients

Broiled or baked fish lowers risk of AF in older adults

Cardiovascular disease in the elderly

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