OBJECTIVE Hypertension is estimated to cause 4.5% of current global disease burden and is as prevalent in many developing countries, as in the developed world. Blood pressure-induced cardiovascular risk rises continuously across the whole blood pressure range. Countries vary widely in capacity for management of hypertension, but worldwide the majority of diagnosed hypertensives are inadequately controlled. This statement addresses the ascertainment of overall cardiovascular risk to establish thresholds for initiation and goals of treatment, appropriate treatment strategies for non-drug and drug therapies, and cost-effectiveness of treatment. CONCLUSIONS Since publication of the WHO/ISH Guidelines for the Management of Hypertension in 1999, more evidence has become available to support a systolic blood pressure threshold of 140 mmHg for even 'low-risk' patients. In high-risk patients there is evidence for lower thresholds. Lifestyle modification is recommended for all individuals. There is evidence that specific agents have benefits for patients with particular compelling indications, and that monotherapy is inadequate for the majority of patients. For patients without a compelling indication for a particular drug class, on the basis of comparative trial data, availability, and cost, a low dose of diuretic should be considered for initiation of therapy. In most places a thiazide diuretic is the cheapest option and thus most cost effective, but for compelling indications where other classes provide additional benefits, even if more expensive, they may be more cost effective. In high-risk patients who attain large benefits from treatment, expensive drugs may be cost effective, but in low-risk patients treatment may not be cost-effective unless the drugs are cheap.

2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension.

http://academic.oup.com/milmed/article-pdf/146/7/506/24126715/milmed-146-7-506.pdf

Goodman and Gilman's The Pharmacological Basis of Therapeutics

Randomized controlled trials often suffer from two major complications, ie, noncompliance and missing outcomes One potential solution to this problem is a statistical concept called intention-to-treat (ITT) analysis ITT analysis includes every subject who is randomized according to randomized treatment assignment It ignores noncompliance, protocol deviations, withdrawal, and anything that happens after randomization ITT analysis maintains prognostic balance generated from the original random treatment allocation In ITT analysis, estimate of treatment effect is generally conservative A better application of the ITT approach is possible if complete outcome data are available for all randomized subjects Per-protocol population is defined as a subset of the ITT population who completed the study without any major protocol violations

Intention-to-treat concept: A review.

We review recent research on the presentation, nosology and epidemiology of behavioral and emotional psychiatric disorders in preschool children (children ages 2 through 5 years old), focusing on the five most common groups of childhood psychiatric disorders: attention deficit hyperactivity disorders, oppositional defiant and conduct disorders, anxiety disorders, and depressive disorders. We review the various approaches to classifying behavioral and emotional dysregulation in preschoolers and determining the boundaries between normative variation and clinically significant presentations. While highlighting the limitations of the current DSM-IV diagnostic criteria for identifying preschool psychopathology and reviewing alternative diagnostic approaches, we also present evidence supporting the reliability and validity of developmentally appropriate criteria for diagnosing psychiatric disorders in children as young as two years old. Despite the relative lack of research on preschool psychopathology compared with studies of the epidemiology of psychiatric disorders in older children, the current evidence now shows quite convincingly that the rates of the common child psychiatric disorders and the patterns of comorbidity among them in preschoolers are similar to those seen in later childhood. We review the implications of these conclusions for research on the etiology, nosology, and development of early onset of psychiatric disorders, and for targeted treatment, early intervention and prevention with young children.

Common emotional and behavioral disorders in preschool children: presentation, nosology, and epidemiology.

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors)
are associated with skeletal muscle complaints, including clinically important
myositis and rhabdomyolysis, mild serum creatine kinase (CK) elevations, myalgia
with and without elevated CK levels, muscle weakness, muscle cramps, and persistent
myalgia and CK elevations after statin withdrawal. We performed a literature
review to provide a clinical summary of statin-associated myopathy and discuss
possible mediating mechanisms. We also update the US Food and Drug Administration
(FDA) reports on statin-associated rhabdomyolysis. Articles on statin myopathy
were identified via a PubMed search through November 2002 and articles on
statin clinical trials, case series, and review articles were identified via
a PubMed search through January 2003. Adverse event reports of statin-associated
rhabdomyolysis were also collected from the FDA MEDWATCH database. The literature
review found that reports of muscle problems during statin clinical trials
are extremely rare. The FDA MEDWATCH Reporting System lists 3339 cases of
statin-associated rhabdomyolysis reported between January 1, 1990, and March
31, 2002. Cerivastatin was the most commonly implicated statin. Few data are
available regarding the frequency of less-serious events such as muscle pain
and weakness, which may affect 1% to 5% of patients. The risk of rhabdomyolysis
and other adverse effects with statin use can be exacerbated by several factors,
including compromised hepatic and renal function, hypothyroidism, diabetes,
and concomitant medications. Medications such as the fibrate gemfibrozil alter
statin metabolism and increase statin plasma concentration. How statins injure
skeletal muscle is not clear, although recent evidence suggests that statins
reduce the production of small regulatory proteins that are important for
myocyte maintenance.

https://jamanetwork.com/journals/jama/articlepdf/196305/JSC20298.pdf

Statin-Associated Myopathy

OBJECTIVE:To determine the number of cases of statin-associated rhabdomyolysis reported to the Food and Drug Administration for 6 statins and to profile the cases.METHODS:A retrospective analysis of all domestic and foreign reports of statin-associated rhabdomyolysis between November 1997 and March 2000 was conducted. Outcome measures included the total number of reports (initial plus follow-up), the number of unique cases, age, gender, percentages of report codes and role codes, and frequencies of concomitant interacting drugs that may have precipitated rhabdomyolysis, outcomes codes, and report source codes.RESULTS:There were 871 reports of statin-associated rhabdomyolysis in the 29-month time frame examined, representing 601 cases. The following number of cases were associated with each of the individual statins: simvastatin, 215 (35.8%); cerivastatin, 192 (31.9%); atorvastatin, 73 (12.2%); pravastatin, 71 (11.8%); lovastatin, 40 (6.7%); and fluvastatin, 10 (1.7%). Drugs that may have interacted with t...

FDA Adverse Event Reports on Statin-Associated Rhabdomyolysis

OBJECTIVE:To review rhabdomyolysis and discuss the role of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) and their interactions with other agents in precipitating this condition, and to present case reports of statin-induced rhabdomyolysis.DATA SOURCE:Relevant clinical literature was accessed using MEDLINE (January 1985–October 2000). The following search terms were used: rhabdomyolysis, adverse events, drug interactions, statins, and HMG-CoA reductase inhibitors.DISCUSSION:Rhabdomyolysis occurs when extensive muscle damage results in the release of cellular contents into systemic circulation. Major complications include acute renal failure, cardiac abnormalities, and compartment syndrome. Treatment of rhabdomyolysis is supportive, with the primary aim of preventing renal and cardiac complications. Statin monotherapy or combination therapy may result in myopathy, which rarely progresses to rhabdomyolysis. The mechanism for drug interactions with the statins involves their prope...

Rhabdomyolysis and HMG-CoA Reductase Inhibitors

Objective To estimate prevalence rates of antipsychotic use in children and adolescents from 1996 to 2001 in three state Medicaid programs (midwestern [MM], southern [SM], and western [WM]) and one private managed care organization (MCO). Method Prescription claims were used to evaluate antipsychotic prevalence, defined as the number of children and adolescents up to the age of 19 years with at least one prescription claim for an antipsychotic per 1,000 enrolled youths. Results From 1996 to 2001, the prevalence of total antipsychotic use increased in each program (MM: 4.7 to 14.3 per 1,000; SM: 6.3 to 15.5; WM: 4.5 to 6.9; and MCO: 1.5 to 3.4). Typical antipsychotic use decreased (MM: 3.7 to 2.0 per 1,000; SM: 4.6 to 1.5; WM: 4.4 to 1.3; and MCO: 1.2 to 0.9), while atypical antipsychotic use dramatically increased (MM: 1.4 to 13.1 per 1,000; SM: 2.5 to 14.9; WM: 0.3 to 6.2; and MCO: 0.4 to 2.7). Conclusions The increased prevalence of antipsychotic use in children and adolescents from 1996 to 2001 was attributed to increased use of atypical antipsychotics. Given the limited data with atypical antipsychotics in youths, this emphasizes the need for additional studies of these agents and other treatment modalities in this population.

Trends in the use of typical and atypical antipsychotics in children and adolescents

Study Objective. To validate or refute a widely accepted epidemiologic phenomenon known as the Weber effect by replicating Weber's original observation by using drugs that were marketed in the United States and using reports from a U.S. database.

Design. Retrospective analysis of adverse event databases.

Setting. University research center.

Drugs. The original nonsteroidal antiinflammatory drugs studied by Weber that were approved by the U.S. Food and Drug Administration (FDA) and marketed in the United States: diclofenac sodium, diclofenac potassium, diflunisal, sulindac, flurbiprofen, and piroxicam.

Intervention. Reports of adverse events submitted to the FDA's Spontaneous Reporting System and the Adverse Event Reporting System from January 1969–December 2000 for these drugs were analyzed according to the number of adverse events reported for each drug per year from the time the drug was approved until December 2000.

Measurements and Main Results. Reporting patterns were considered to demonstrate the Weber effect if the highest peak in reports during the first 5 years after product approval occurred during year 2. All five drugs analyzed in this study demonstrated the Weber effect.

Conclusion. The Weber effect was replicable by using drugs marketed in the United States and using reports that were submitted to a U.S. database. Various other factors affected spontaneous reporting of adverse events, as peaks in the number of reports were seen numerous times for each drug after the initial 5-year marketing period.

Replication of the Weber Effect Using Postmarketing Adverse Event Reports Voluntarily Submitted to the United States Food and Drug Administration

Study Objective. To examine adherence measures with different stimulants in children and adolescents.



Design. Retrospective analysis.



Data Source. Texas Medicaid prescription claims database.



Patients. A total of 9549 patients aged 5–18 years with attention-deficit—hyperactivity disorder.



Measurements and Main Results. Paid prescription claims for newly started stimulants during the 2001–2002 school year were extracted from a database; 28,344 prescriptions (9549 patients) were available for analysis. Adherence was evaluated based on the drug therapy prescribed (i.e., mixed amphetamine salts, immediate-release methylphenidate, and extended-release methylphenidate—OROS [oral-osmotic formulation]) and the age and sex of the patient. Adherence measures were persistence and medication possession ratio (MPR). Persistence was higher for extended-release methylphenidate—OROS (0.50 ± 0.33) than for mixed amphetamine salts (0.42 ± 0.29) or immediate-release methylphenidate (0.37 ± 0.26; p<0.001). The MPR was also higher for extended-release methylphenidate—OROS (0.76 ± 0.37) than for mixed amphetamine salts (0.73 ± 0.37) or immediate-release methylphenidate (0.69 ± 0.37; p<0.001). Patients aged 5–9 years had equal or better persistence and MPR than those aged 10–14 and 15–18 years (p<0.001). No sex-related differences in adherence were observed.



Conclusion. Adherence measures in our study were low. Although they were significantly better for extended-release methylphenidate—OROS than the other stimulants, the clinical significance of these differences are unclear. Further research should be conducted regarding pharmaceutical products, administration methods, and clinical interventions that may enhance adherence.

James P. Wilson

Papers

FDA Adverse Event Reports on Statin-Associated Rhabdomyolysis

Rhabdomyolysis and HMG-CoA Reductase Inhibitors

Trends in the use of typical and atypical antipsychotics in children and adolescents

Replication of the Weber Effect Using Postmarketing Adverse Event Reports Voluntarily Submitted to the United States Food and Drug Administration

Assessment of adherence measures with different stimulants among children and adolescents.