A 'polypill' aimed at preventing cardiovascular disease could prove highly cost-effective for use in Latin America.

We evaluated the cost-effectiveness of administering a daily "polypill" consisting of three antihypertensive drugs, a statin, and aspirin to prevent cardiovascular disease among high-risk patients in Latin America. We found that the lifetime risk of cardiovascular disease could be reduced by 15 percent in women and by 21 percent in men if the polypill were used by people with a risk of cardiovascular disease equal to or greater than 15 percent over ten years. Attaining this goal would require treating 26 percent of the population at a cost of $34-$36 per quality-adjusted life-year. Offering the polypill to women at high risk and to men age fifty-five or older would be the best approach and would yield acceptable incremental cost-effectiveness ratios. The polypill would be very cost-effective even in the country with the lowest gross national income in our study. However, policy makers must weigh the value of intervention with the polypill against other interventions, as well as their country's willingness and ability to pay for the intervention.

Persistence with nebivolol in the treatment of hypertension: a retrospective claims analysis.

OBJECTIVE: Examine drug persistence by evaluating the hazard of discontinuation and of switching to different antihypertensive drugs in patients initiating treatment with a recently approved ß-blocker, nebivolol, versus other ß-blockers. METHODS: This retrospective analysis included all patients diagnosed with hypertension in the MarketScan Database (January 2007 - December 2008) with at least two medical claims and no prior ß-blocker prescriptions within 6 months of the initial prescription date. Multivariate Cox proportional hazard models (adjusted for baseline differences in demographics, previous use of other antihypertensive medications, initial doses and supply of medication, and number of distinct prescriptions at baseline) were used to assess the hazard of discontinuation, defined as the first prescription gap of ≥30 days, and to assess the hazard of switching to another antihypertensive drug, defined as a prescription fill for another antihypertensive drug within 15 days before and 30 days after discontinuation of the initial ß-blocker. RESULTS: Of the 173,200 patients included in the study population, the adjusted hazard of discontinuation for nebivolol-initiated patients was 8-20% lower than that of patients who initiated treatment with atenolol (hazard ratio [HR] 0.82, p < 0.001), metoprolol (HR 0.91, p < 0.001), carvedilol (HR 0.92, p < 0.001), or other ß-blockers (HR 0.80, p < 0.001). The adjusted hazard of nebivolol-treated patients switching to a different antihypertensive medication was 12-22% lower than that of the other four ß-blocker cohorts (atenolol: HR 0.80, p < 0.001; metoprolol: HR 0.86, p < 0.001; carvedilol: HR 0.88, p < 0.001; other ß-blockers: HR 0.78, p < 0.001). Sensitivity analyses defined discontinuation as prescription gaps of ≥45 days and ≥60 days and showed a lower hazard of discontinuation among patients initiating nebivolol than among patients initiating all other drug cohorts (p < 0.001). LIMITATIONS: Comparisons of non-randomized treatment groups may be confounded by unobserved differences in patients' baseline characteristics. CONCLUSIONS: Initiation with nebivolol was associated with greater persistence than initiation with atenolol, carvedilol, metoprolol, or other ß-blockers.

[Clinical-pharmacoeconomical aspects of ß-adrenoblockers use in patients with ischemic heart disease undergoing coronary artery bypass grafting].

Aim of this study was to assess clinical and pharmacoeconomic effects of long term use of adrenoblockers in patients with ischemic heart disease (IHD) undergoing coronary artery bypass grafting. Patients with IHD (n=294) were included in open, prospective, randomized clinical trial. The follow up period was 3 years. It was noted that long term use of bisoprolol in comparison with atenolol and metoprolol was characterized by more pronounced increase of exercise tolerance, lower rate of angina recurrence and lower expenses for treatment of patients with IHD.

Availability, price and affordability of cardiovascular medicines: a comparison across 36 countries using WHO/HAI data.

BACKGROUND: The global burden of cardiovascular disease (CVD) continues to rise. Successful treatment of CVD requires adequate pharmaceutical management. The aim was to examine the availability, pricing and affordability of cardiovascular medicines in developing countries using the standardized data collected according to the World Health Organization/Health Action International methodology. METHODS: The following medicines were included: atenolol, captopril, hydrochlorothiazide, losartan and nifedipine. Data from 36 countries were analyzed. Outcome measures were percentage availability, price ratios to international reference prices and number of day's wages needed by the lowest-paid unskilled government worker to purchase one month of chronic treatment. Patient prices were adjusted for inflation and purchasing power, procurement prices only for inflation. Data were analyzed for both generic and originator brand products and the public and private sector and summarized by World Bank Income Groups. RESULTS: For all measures, there was great variability across surveys. The overall availability of cardiovascular medicines was poor (mean 26.3% in public sector, 57.3% private sector). Procurement prices were very competitive in some countries, whereas others consistently paid high prices. Patient prices were generally substantially higher than international references prices; some countries, however, performed well. Chronic treatment with anti-hypertensive medication cost more than one day's wages in many cases. In particular when monotherapy is insufficient, treatment became unaffordable. CONCLUSIONS: The results of this study emphasize the need of focusing attention and financing on making chronic disease medicines accessible, in particular in the public sector. Several policy options are suggested to reach this goal.

Ivabradine: new drug. Best avoided in stable angina.

(1) The first-line symptomatic treatment for stable angina is a betablocker such as atenolol. Some calcium channel blockers such as verapamil, and the potassium channel agonist amlodipine, are second-line alternatives. Long-acting nitrate derivatives have poorly documented efficacy but can be used as adjuvants or as third-line treatments. (2) Ivabradine is derived from verapamil but appears to have a different mechanism of action, mainly lowering the heart rate. It was approved for sale in Europe through the centralised procedure for second-line treatment of stable angina. (3) Clinical evaluation of ivabradine only includes randomised controlled trials versus two other anti-angina drugs: atenolol and amlodipine. Three double-blind randomised controlled trials lasting 3 to 4 months, based on surrogate exercise endpoints, failed to show that ivabradine was any more effective than atenolol or amlodipine, or even more effective than placebo in patients already treated with amlodipine. (4) In two one-year double-blind randomised controlled trials comparing ivabradine with atenolol or amlodipine in a total of 704 patients, ivabradine was no more effective than the comparators in preventing angina attacks. (5) In head-to-head comparisons, serious coronary events were significantly more frequent with ivabradine than with atenolol (3.8% versus 1.5%). Severe arrhythmias were also more frequent with ivabradine than with atenolol (1.3% versus 0.7%) or amlodipine (0.6% versus 0.2%). (6) Ivabradine provokes phosphenes (flashing lights, etc.) in about 17% of patients in the short term. Information is inadequate to assess possible risks of retinal toxicity in the long term. (7) Ivabradine is metabolised by cytochrome P450 isoenzyme CYP 3A4; there is therefore a potentially high risk of pharmacokinetic interactions. (8) In practice, for long-term preventive treatment of angina it is better to avoid ivabradine and to use better-documented treatments: preferably a betablocker, or, if a betablocker cannot be used, verapamil or amlodipine.

Cost-effectiveness of differing perioperative beta-blockade strategies in vascular surgery patients.

OBJECTIVES: To determine the incremental value of different strategies of both oral and intravenous beta-blockade during the perioperative period in high-risk vascular patients in reducing costs and improving outcomes. DESIGN: Decision analytic model incorporating costs from provider's perspective INTERVENTIONS: Five perioperative strategies in patients undergoing abdominal aortic aneurysm surgery: (1). no routine beta-blockade, (2). preoperative oral bisoprolol for 7 days followed by perioperative intravenous metoprolol and oral bisoprolol based on preoperative titration, (3). immediate preoperative atenolol with postoperative intravenous then oral atenolol, (4). intraoperative esmolol and postoperative intravenous then oral atenolol, and (5). intraoperative and 18 hours of postoperative esmolol then atenolol. MEASUREMENTS AND MAIN RESULTS: Perioperative death was associated with a net increase of US dollars 21909 in charges to Medicare, whereas sustaining a perioperative myocardial infarction was associated with a net increase in charges of US dollars 15000. There is a net hospital saving of US dollars 500 using a strategy of titration of an oral beta-blocker medication for a minimum of 7 days, with a net increase in efficacy of 0.0304. All of the strategies involving acute perioperative blockade were associated with a net cost savings and increase in efficacy, although less than the strategy involving preoperative oral titration. CONCLUSION: Perioperative beta-blockade is both cost effective as well as efficacious from a short-term provider perspective. The optimal strategy of treatment for patients who do not present to surgery already on beta-blockers requires further study, although all strategies save money even accounting for pharmaceutical costs.

The prognostic and economic implications of a strategy to detect and treat asymptomatic ischemia: the Atenolol Silent Ischemia Trial (ASIST) protocol.

Although silent ischemia may be linked to increases in cardiovascular morbidity and mortality, the long-term effects of a strategy aimed at the detection and treatment of this asymptomatic condition have not been fully explored. We therefore have developed the Atenolol Silent Ischemia Trial (ASIST), the first multicenter, randomized, prospective study of the prognostic implications of silent ischemia in asymptomatic and minimally symptomatic patients with coronary artery disease. Inclusion criteria for study patients were documented coronary artery disease, evidenced angiographically or by previous myocardial infarction, and transient ischemia, evidenced by abnormalities of regional wall motion, stress thallium-201, or exercise electrocardiogram. The main objective of ASIST is to assess the influence of frequency and duration of symptomatic and asymptomatic ischemic episodes on the occurrence of fatal and nonfatal cardiac events. Atenolol, a beta 1-selective adrenergic blocker, was chosen as the therapeutic intervention because of its potential benefits in treating both symptomatic and asymptomatic ischemia. Ambulatory electrocardiographic monitoring will be used to measure the frequency and duration of ischemic episodes during daily life. The predictive ability of short-term (4-week) effects on long-term (52-week) response to atenolol treatment is also being assessed, along with the economic impact of this diagnostic and therapeutic strategy. Given the current emphasis on reducing morbidity and mortality associated with coronary artery disease, ASIST results should shed light onto the long-term management and prognostic implications of this otherwise asymptomatic condition.

Assessment of quality of life by patient and spouse during antihypertensive therapy with atenolol and nifedipine gastrointestinal therapeutic system.

To evaluate differences in efficacy, safety, and quality of life, 394 male patients with mild-to-moderate hypertension were randomized to receive 20 weeks of either atenolol or nifedipine gastrointestinal therapeutic system (GITS) in a multicenter double-blind trial. A four-week placebo washout was followed by 8 weeks of titration and 12 weeks of maintenance therapy. Quality-of-life evaluation included clinical assessments by the patient and parallel take-home assessments by patient and spouse. Blood pressure was controlled equally in both groups. The total incidence of adverse reactions was similar in both groups, but a greater percentage of nifedipine GITS patients withdrew due to peripheral edema. Patients completing 20 weeks of therapy demonstrated a more favorable quality-of-life profile (P less than .05) for nifedipine GITS over atenolol in psychosocial (P less than .01), well-being (P less than .05), general affect (P less than .05), emotional ties (P less than .01), emotional control (P less than .05), vitality (P less than .05), and leisure (P less than .05) scores. Treatment differences were particularly pronounced for patients over 50 years of age and were not fully detectable until after 14 weeks of therapy. Deterioration in quality of life was associated with withdrawal. Spouses of younger patients receiving atenolol reported deterioration in sexual satisfaction as compared to spouses of patients taking nifedipine GITS (P less than .02). Thus age, length of trial, and third-party observation are important factors in quality-of-life assessment. Comparison of adverse reactions provides an incomplete measure of how well a drug is tolerated. In contrast, findings indicate that even subtle CNS-mediated effects on mood and well-being can be detected by quality-of-life evaluation.

Assessment of beta-1 selectivity of bisoprolol and atenolol by means of their influence on the lipolytic response to an infusion of terbutaline.

We have investigated the beta-1 selectivity of a new beta-blocker, Bisoprolol, by comparing its effect on lipolysis induced by intravenous terbutaline infusion with that of Atenolol. At a dose of 5 mg, Bisoprolol had virtually no beta-2 blocking activity as measured by free fatty acid (FFA) release during terbutaline infusion. At a dose of 10 mg, Bisoprolol had a small but statistically insignificant effect on FFA release similar to 50 mg Atenolol. At a dose of 20 mg, Bisoprolol had significant beta-2 blocking activity. At lower doses, therefore, Bisoprolol is a very selective beta-blocker.

Assessment of a fixed-dosage combination of atenolol and chlorthalidone (Tenoretic) in hypertensive Nigerians.

The antihypertensive effect of a fixed dosage combination of the cardioselective beta-adrenoceptor blocker, atenolol, and the oral thiazide-like diuretic, chlorthalidone (Tenoretic) was studied in 24 hypertensive Nigerians in a double-blind, cross-over comparison with three other treatments. These were atenolol alone, 100 mg daily, chlorthalidone alone, 25 mg daily, and atenolol (100 mg) plus chlorthalidone (25 mg) daily taken as separate formulations. Tenoretic was taken as a once-daily tablet containing 100 mg atenolol plus 25 mg chlorthalidone. The order of administration of the drugs was randomized. Each drug was taken for 4 weeks. The results showed that atenolol and chlorthalidone lowered blood pressure to the same extent. Combination of the two drugs whether taken separately or in fixed-dosage combination was better than either product singly. The drugs were well tolerated.

Hemodynamic assessment of nicardipine alone and with atenolol in coronary artery disease using a modified echo-Doppler device.

We have used a modified noninvasive echo-Doppler cardiac output device, based on the principle of attenuated compensation volume flow, to assess the cardiovascular effects of the slow-calcium antagonist nicardipine in coronary disease. The dose-response effects of 2.5, 5.0 and 10.0 mg intravenous nicardipine were determined in 8 patients with angina. Dose-related decreases were seen in systemic mean arterial pressure (p less than 0.01) after administration of nicardipine. Cardiac pumping indexes were improved, as evident from linear increases in cardiac stroke volume (p less than 0.001), stroke length (p less than 0.01) and time-averaged mean velocity (p less than 0.01). The echo-Doppler device was also used to assess beta-blocking/nicardipine combination therapy in patients with angina. When nicardipine was given after the cardioselective beta blocker atenolol the reduction in heart rate and cardiac output after atenolol was reversed compared with a group that received atenolol followed by placebo. Cardiac performance improved and the 35% reduction in systemic vascular resistance was associated with markedly increased cardiac index (p less than 0.01), augmentation of time-averaged mean velocity (p less than 0.01) and cardiac stroke length (p less than 0.05). These data are consistent with previous invasive studies of nicardipine, either alone or when combined with beta blockade in coronary disease. The data also suggest that nicardipine/beta-blocking combination is safe in patients with coronary heart disease and that the echo-Doppler method of cardiovascular monitoring will prove useful in human pharmacodynamic studies.