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A topical agent is usually example generic tadora 20 mg without prescription impotence smoking, most of the campaigns conducted to described as a vehicle and an active substance buy generic tadora line erectile dysfunction causes divorce, increase the public awareness of skin cancer have the vehicles being classified as powder buy discount tadora 20mg on-line erectile dysfunction natural remedy, grease, led to a large increase in the number of benign liquid or combinations such as pastes and creams. Most of these different countries in terms of health service products seem to rely on physical rather than organisation for treating skin disorders. Physical 1:20 000 in Italy and France to 1:150 000 in the effects of topical agents may include detersion, United Kingdom. Pharmacists occupy a key role It should be noted that the evaluation of even the in advising the public on the use of over- most recent cosmetic products is far from being the-counter products. In addition to pharmacological treat- seem to treat the majority of people among ment, a number of non-pharmacological treat- those seeking medical advice. Primary care of ment modalities exists including phototherapy dermatological problems seems to be imprecisely or photochemotherapy and minor surgical proce- defined with a large overlap with specialist dures such as electrodessication and criotherapy. In spite of the vast number of dermatological diseases, it has been documented that just a few categories account for about 70% ACNE of all dermatological consultations. Brief, more detailed descriptions of the most frequent skin the term acne refers to a group of disorders categories are given below while skin cancer is characterised by abnormalities of the sebaceous dealt with in another section. Acne vulgaris is the most common Generally speaking, dermatology requires a condition and is characterised by polymor- low technology clinical practice. Clinical exper- phous lesions, including comedones (black- tise is mainly dependent on the ability to recog- heads), inflammatory lesions such as papules or nise a skin disorder quickly and reliably which, pustules, and scars, affecting the face and less fre- in turn, depends to a large extent on the aware- quently the back and shoulders. A combination of ness of a given clinical pattern, based on pre- factors are considered as pathogenetic, including vious experience and on the exercised eye of a the hormonal influence of androgens, seborrhea, visually literate physician. Mild degrees of acne 214 TEXTBOOK OF CLINICAL TRIALS are extremely common amongst teenagers (more two to threefold over the last 30 years. The preva- some evidence that it may be possible to prevent lence of moderate to severe acne has been esti- atopic dermatitis in high-risk children born to par- mated at about 14% in 15–24 year-olds, 3% in ents with atopic disease by restricting maternal 25–34 year-olds and about 1% in 35–54 year- allergens and reducing house dust mite levels. It is likely that the vast majority of suf- No treatment has been shown to alter the natural ferers of mild acne do not seek medical advice. Criteria for treatment include clinical sever- ity, as judged by the extension and presence of inflammatory lesions, and the degree of psycho- PSORIASIS logical distress from the disease. The aim of treatment is to prevent scarring, limit disease This is a chronic inflammatory disorder charac- duration and reduce psychological stress. Mild terisedbyredscalyareas,whichtendtoaffect acne is usually treated by topical modalities such extensory surfaces of the body and scalp. Its as benzoyl peroxide or tretinoin, while moderate overall prevalence is about 1–3% and males are severity acne is treated by systemic antibiotics or affected more frequently than females. Oral isotretinoin is used varieties have been described including guttate, under specialist supervision for severe unrespon- pustular and erythrodermic psoriasis. There are a number of published 3% of cases it may associate with a peculiar systems for measuring the severity of acne. Significant disability has been docu- These vary from sophisticated systems with up mented with psoriasis. Multifactorial heredity is to 100 potential grades to simple systems with 4 usually considered for disease causation. A specially designed acne disability implies interaction between a genetic predispo- index has also been devised to assess the psycho- sition and environmental factors. Heritability, a logical impact of the disease and disability, and measure that quantifies the overall role of genetic has been found to correlate well with severity as factors, ranges from 0. Acute infections, measured by an objective grading system, even physical trauma, selected medications and psy- if a small group experiences disability which is chological stress are usually viewed as triggers. Sun exposure usually tem- ATOPIC DERMATITIS porarily improves the disease. Typically, this condition is characterised by itch- the lesions are visible and may itch, sting and ing, dry skin and inflammatory lesions especially bleed easily. Patients suffering from short-term suppression of symptoms and long- atopic dermatitis may also develop IgE-mediated term modulation of disease severity, improving allergic diseases such as bronchial asthma or the quality of life with minimal side effects. An overall cumulative preva- Topical agents such as vitamin D derivatives, lence of between 5% and 20% has been suggested dithranol and steroids can be used for short-term by the age of 11. Ultraviolet B phototherapy, clear of significant disease by their mid-teens. Outcomes DERMATOLOGY 215 that matter to the patient include disease suppres- the UK proved to offer advantages over home sion and duration of remission, patient satisfac- treatment. METHODS: ADAPTING STUDY DESIGN TO In the long term, a simple measure such as the SETTING AND DISEASE number of patients reaching complete or nearly complete stable remission appears as the most As for other disciplines, the last few decades relevant outcome variable. LEG ULCERS However, there are indications that the upsurge of clinical research has not been paralleled by a Venous and arterial leg ulcers are recognised refinement in clinical trial methodology and the as the most common chronic wounds in West- quality of randomised control trials (RCTs) in ern populations. A skin ulcer has been defined dermatology falls well below the usually accepted standards. Ulcers persisting for to mention some issues which deserve special 4 weeks or more have been rather arbitrarily attention when designing a randomised clinical classified as chronic ulcers. There is a need tion surveys, the point prevalence of leg ulcers for innovative thinking in dermatology to make ranges from 0. Venous ulcers are the end result of super- not simply ape the scientific design. Arte- RANDOMISATION rial ulceration may be regarded as a multistep process, starting, in general, with a systemic vas- It can be estimated that there are at least cular derangement such as atherosclerosis. The a thousand rare or very rare skin conditions prognosis of leg ulcers is less than satisfactory, where no single randomised trial has been with about one-quarter of subjects not healing in conducted. These conditions are also those which over 2 years and the majority of patients hav- carry a higher burden in terms of physical ing recurrence. The annual incidence the healing time varied according to the dimen- rate of many of them is lower than 1 case sion of the ulcers, their duration and the mobil- per 100 000 and frequently less than 1 case ity of the patient. There are lation, depression and negative self-image have no examples of such an effort. These con- patients in the community, including the lack of ditions include several varieties of eczematous any clinical assessment leading to long periods of dermatitis. One alleged difficulty with mounting riasis lesions, and a maintenance phase, with the randomised clinical trials in dermatology is the main aim of preventing disease relapse. The dif- visibility of skin lesions and the consideration ferent phases are not necessarily well separated that much more than in other areas, patients in time. Long-term disease-modifying strategies self-monitor their disease and may have precon- can be adopted at the same time when a treat- ceptions and preferences about specific treatment ment modality for reaching clearance has been modalities. An example is the treatment of atopic tated by subjective issues and personal feelings. Most ran- As we will consider below, there is a need to edu- domised clinical trials in dermatology use a sim- cate physicians and the public about the value of plified approach to evaluating treatment effects randomised trials to assess interventions in der- and most of them analyse the effect of a single matology. The need to evaluate the attitudes of manoeuvre over a limited time span. One as yet patients and to educate should be clearly con- not fully explored issue is the potential for com- sidered when planning a study and developing bining different treatment approaches in a simul- modalities to obtain an informed consent from taneous or subsequent order. An example als there may be substantial differences in group of such a design would be a randomised clin- sizes that will reduce the precision of the esti- ical trial of the effect of a low-allergen diet mated differences in treatment effect and hence compared with an unrestricted diet in atopic the efficiency of the study. As a consequence, women during pregnancy and breast-feeding on block randomisation may be preferable.

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First discount tadora 20 mg line impotence specialists, the client and family need to their use and must be used with caution in clients with hepatic be able and willing to manage some aspects of therapy and impairment discount 20 mg tadora free shipping erectile dysfunction pills cost. Second purchase genuine tadora on-line erectile dysfunction treatment natural in india, arrange- Some fluoroquinolones have been associated with liver en- ments must be made for procuring equipment, supplies, and zyme abnormalities and hepatotoxicity (eg, hepatitis, liver im- medication. The drugs should be used cautiously in companies help families prepare and use IV infusion pumps. The drug should be stopped if jaundice or any other symp- unit-dose package ready for administration. CHAPTER 33 GENERAL CHARACTERISTICS OF ANTIMICROBIAL DRUGS 507 the role of the home care nurse includes teaching the continuous infusion, whether the client has a peripheral or client and caregiver to store and administer the medication, central IV line, and other factors. The family should be pro- monitor the IV site, monitor the infection, manage problems, vided with detailed instructions and emergency telephone and report client responses. Specific responsibilities may numbers of the home care nurse, the pharmacy, and the sup- vary according to drug administration intermittently or by ply company. NURSING Antimicrobial Drugs ACTIONS NURSING ACTIONS RATIONALE/EXPLANATION 1. Give most oral antimicrobials on an empty stomach, To decrease binding to foods and inactivation by gastric acid approximately 1 h before or 2 h after meals. For oral and parenteral solutions from powder forms, follow Several antimicrobial drugs are marketed in powder forms because label instructions for mixing and storing. When mixed, measured amounts of diluent must be added for drug dissolution and the appropriate concentration. None of the solutions should be used after the expiration date because drug decomposition is likely. Give parenteral antimicrobial solutions alone; do not mix To avoid chemical and physical incompatibilities that may cause with any other drug in a syringe or intravenous (IV) solution. Give intramuscular (IM) antimicrobials deeply into large To decrease tissue irritation muscle masses (preferably gluteal muscles), and rotate injec- tion sites. For IV administration, use dilute solutions, give direct in- Most antimicrobials that are given IV can be given by intermittent jections slowly and intermittent infusions over 30 to 60 min. Although instructions vary with specific drugs, most re- After infusions, flush the IV tubing with at least 10 mL of IV constituted drugs can be further diluted with 50 to 100 mL of IV solution. For children, check references about individual drugs fluid (D W, NS, D -1⁄ % or D -1⁄ % NaCl). Dilution and slow ad- 5 5 4 5 2 to avoid excessive concentrations and excessive fluids. Flushing ensures that the entire dose is given and prevents contact between drugs in the tubing. With local infections, observe for decreased redness, Signs and symptoms of inflammation and infection usually sub- edema, heat, and pain. With systemic infections, observe for decreased fever and regardless of the cause, local manifestations vary with the type or white blood cell count, increased appetite, and reports of feel- location of the infection. With wound infections, observe for decreased signs of local inflammation and decreased drainage. With respiratory infections, observe for decreased dyspnea, coughing, and secretions. With urinary tract infections, observe for decreased ur- gency, frequency, and dysuria. If urinalysis is done, check the laboratory report for decreased bacteria and white blood cells. Hypersensitivity Reactions are more likely to occur in those with previous hyper- sensitivity reactions and those with a history of allergy, asthma, or hay fever. Anaphylaxis may occur with oral administration but is more likely with parenteral administration and may occur within 5 to 30 min of injection. Superinfection Superinfection is a new or secondary infection that occurs during antimicrobial therapy of a primary infection. Superinfections are common and potentially serious because responsible microorgan- isms are often drug-resistant staphylococci, gram-negative organ- isms (eg, Pseudomonas aeruginosa), or fungi (eg, Candida). These and other antibiotics suppress normal bacterial flora and allow the over- growth of Clostridium difficile. The organism produces a toxin that kills mucosal cells and produces superficial ulcerations that are visible with sigmoidoscopy. Discontinuing the drug and giving metronidazole or oral vancomycin are curative measures. Phlebitis at IV sites; pain at IM sites Many antimicrobial parenteral solutions are irritating to body tissues. Nausea and vomiting These often occur with oral antimicrobials, probably from irritation of gastric mucosa. Diarrhea Commonly occurs, caused by irritation of gastrointestinal mu- cosa and changes in intestinal bacterial flora; and may range from mild to severe. Nephrotoxicity (1) See AIN, earlier More likely to occur in clients who are elderly or who have impaired renal function. Neurotoxicity—confusion, hallucinations, neuromuscular More likely with large IV doses of penicillins or cephalosporins, irritability, convulsive seizures especially in clients with impaired renal function. Bleeding—hypoprothrombinemia, platelet dysfunction Most often associated with penicillins and cephalosporins. The most significant interactions are those that alter effectiveness or increase drug toxicity. CHAPTER 33 GENERAL CHARACTERISTICS OF ANTIMICROBIAL DRUGS 509 SELECTED REFERENCES Review and Application Exercises Abate, B. Louis: Facts and spectrum of activity, and minimum inhibitory concen- Comparisons. Why are infections of the brain, eye, and prostate gland Clinical relevance, therapy, and prevention. What factors promote the development of drug-resistant Control and Hospital Epidemiology, 20(4), 247–278. Hospital-acquired infections: Realities of risks and microbial drug therapy? When a dose of an antibiotic is prescribed to prevent microbial pharmacotherapy. What special precautions are needed for clients with in the ICU: the growing importance of antibiotic-resistant pathogens. Discuss similarities and differences between ness, safety, spectrum of antimicrobial activ- cephalosporins and penicillins. Differentiate cephalosporins in relation to administration, observation of client response, antimicrobial spectrum, indications for use, and teaching of clients. Apply principles of using beta-lactam anti- initial dose of a penicillin. Critical Thinking Scenario Kurt, 5 months of age, is brought to the urgent care center at 4 am. He has had a cold for 3 days and started to run a high temperature (over 39°C) last evening. He has been crying continuously for the last 8 hours and appears to be in pain.

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Study outcomes: In the treatment group purchase cheap tadora on line impotence nitric oxide, 16 cases were cured cheap tadora 20mg fast delivery erectile dysfunction injection therapy, 12 cases improved purchase tadora canada erectile dysfunction treatment thailand, and two cases had no improvement. In the comparison group, five cases were cured, 17 cases improved, and eight cases had no improvement. From A Clinical Study & Comparison on the Use of Varied Forms of Acupuncture & Massage for the Treatment of Occult Spina Bifida Enuresis by Hu Jun-xia et al. These patients were randomly divided into two equal groups—an acupuncture and massage treatment group and a Chinese medicine comparison group. Treatment method: the main acupoints for all members of the treatment group in Chinese Research on the Treatment of Pediatric Enuresis 143 order to supplement the kidneys, secure and contain were: Guan Yuan (CV 4) Shen Shu (Bl 23) Pang Guang Shu (Bl 28) Qi Jie Gu (Seven Joints & Bones) the area where the spina bifida was located Supplementation method was used on Guan Yuan, Shen Shu, and Pang Guang Shu, and the needles were retained for 15 minutes. After acupuncture, the lesser thenar eminence was used to rub Qi Jie Gu until it was red. After this, the area of the occult spina bifida was pressed and stretched. For members of the comparison group, the main points were: Shen Shu (Bl 23) Qi Jie Gu (Seven Joints & Bones) the area where the spina bifida was located Supplementation method was used at Shen Shu, and the nee- dles were retained for 15 minutes. However, the needles were stimulated only one time throughout the treatment. After acupuncture, Qi Jie Gu was rubbed with the lesser thenar emi- nence until red, and the area of the spina bifida was pressed and stretched. In both groups, treatment was given every other day, and 10 days equaled one course of treatment. It was also suggested that all other treatments for this disorder be discontinued during the treatment period. Study outcomes: In the treatment group, 16 cases were cured, 10 cases improved, and four cases had no improvement. In the comparison group, 15 cases were cured, 12 cases improved, and three cases had no improvement. From the Treatment of 36 Cases of Enuresis [By Comparing Acupuncture] to the Combination of Acupuncture and Zhi Yi San (Stop Loss [of Urine] Powder) by Yu Qing-zhi & Yu Yang, Zhong Yi Wai Zhi Za Zhi (The Chinese Medicine Journal of External Treatments), 2002, #6, p. The Chinese medicine group consisted of 18 cases all between the ages of 3-15 years old. Treatment method: All patients in both groups took the Chinese medicinals, but the first group also received acupuncture in addition to the herbs. Acupoints consisted of the following points: Guan Yuan (CV 4) Zhong Ji (CV 3) San Yin Jiao (Sp 6) Zu San Li (St 36) Bai Hui (GV 20) Zu Yun Gan Qu (Foot Motor Sensory Area on the scalp), bilateral the needles were retained in these points for 30-40 minutes. This treatment was done one time each day, and 10 days equaled one course of treatment. The Chinese medicinal formula taken by both the acupuncture and the Chinese medicine group was composed of: Fu Zi (Radix Lateralis Praeparatus Aconiti Carmichaeli) Rou Gui (Cortex Cinnamomi) Yi Zhi Ren (Fructus Alpiniae Oxyphyllae) Tu Si Zi (Semen Cuscutae) Wu Yao (Radix Linderae) Shan Yao (Radix Dioscoreae) Long Gu (Os Draconis) Wu Wei Zi (Fructus Schisandrae) Mu Li (Concha Ostreae) Chinese Research on the Treatment of Pediatric Enuresis 145 Shi Hu (Herba Dendrobii) Gan Cao (Radix Glycyrrhizae) the dosages of the above medicinals were based on the age and size of the child. These medicinals were decocted in water and taken in three divided doses per day, with 10 days equaling one course of treatment. Study outcomes: In the acupuncture group, 28 cases were cured, five cases markedly improved, two cases improved, and one case did not improve. In the Chinese medicine group, five cases were cured, 11 cases improved, and two cases did not improve. From Comparing the Treatment Results of Using Scalp Acupuncture, Hand Acupuncture & Chinese Medicinals in the Treatment of 129 Cases of Pediatric Enuresis by Huang Wei et. Eighty-one cases were less than eight years old, 42 cases were between 8-11 years old, and six cases were more than 11 years old. The course of disease was one year or less in 37 cases, 1-5 years in 71 cases, and more than five years in 21 cases. Sixty-one cases had enuresis on average one time per night, 43 cases had enuresis every other night, and 25 cases had enuresis three times per week. These 129 cases were randomly divided into three groups – a treatment group of 65, a comparison group #1 of 32, and a comparison group #2 also of 32. Treatment method: All members of the treatment group received scalp acupuncture at Zu Yun Gan Qu (Foot Motor Sensory Area) bilaterally. This point is located on the crown of the head one centimeter 146 Treating Pediatric Bed-wetting with Acupuncture & Chinese Medicine anterior from the center on the midline. The point is three cen- timeters parallel to the midline anterior and posterior from this point. This area corresponds to the transverse line on the crown of the head found in standardized international scalp acupunc- ture. After a quick insertion below the skin, the needle was slowly moved to a depth of three centimeters transversely. The needle was stimu- lated at a rate of 200 times per minute, and this was performed every 3-5 minutes. The needles were retained for 5-10 minutes and were removed after the third time the needles were manipu- lated. This treatment was given every other day, and 10 treat- ments equaled one course. Ye Niao Dian (Enuresis Point) was needled bilaterally using a half inch, 30 gauge filiform needle. The needles were manipulated until the child felt distention and then the needles were retained for 30-45 minutes. This treatment was administered one time every other day, and 10 times equaled one course of treatment. All members of comparison group #2 were administered the fol- lowing Chinese medicinals: Sang Piao Xiao (Ootheca Mantidis) Yuan Zhi (Radix Polygalae) Shi Chang Pu (Rhizoma Acori Tatarinowii) Long Gu (Os Draconis) Fu Shen (Sclerotium Pararadicis Poriae Cocos) Ren Shen (Radix Ginseng) Dang Gui (Radix Angelicae Sinensis) vinegar mix-fried Gui Ban (Plastrum Testudinis) Three to 10 grams of each medicinal was used according to the age of the patient. One packet of these medicinals was decocted in water and administered per day, with 10 days equaling one course of treatment. Study outcomes: the following table shows the outcomes of these three groups. Chinese Research on the Treatment of Pediatric Enuresis 147 NO AMELIORATION NUMBER CURE (%) IMPROVEMENT IMPROVEMENT RATE OF CASES (%) (%) (%) Treatment 65 53 (81. From A Comparison Study & the Clinical Results of Treating Kidney Qi Insufficiency Pattern Enuresis with Moxibustion on Medicinal Cakes and Acupuncture by Jiang He-xin, Shang Hai Zhong Yi Yao Za Zhi (Shanghai Journal of Chinese Medicine & Medicinals), 1998, #5, p. These 220 patients were randomly divided into a moxibustion on medicinal cake group and an acupuncture group. The moxibustion on medicinal cake group consisted of 120 cases, 67 males and 53 females, with an average age of nine years old. The course of disease in this group ranged from four months to 10 years. The acupuncture group was comprised of 100 cases, 54 males and 46 females, with an average age of 8. The course of disease in this group ranged from five months to 11 years. Other signs and symptoms includ- ed a bright white facial complexion, devitalized essence spirit, a cold body and chilled limbs, a pale tongue with white fur, and a deep, slow, forceless pulse. Urine tests were normal in all cases, and x-ray showed no abnormalities. Children had to be more than three years old to be enrolled in this study.

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J Natl Cancer Inst (1995) donidis C buy tadora 20mg low cost erectile dysfunction treatment comparison, Albain KS generic tadora 20mg without prescription erectile dysfunction age 80, Brahmer JR order line tadora erectile dysfunction medication with no side effects, Sandler A, 87: 183–90. One-sample multiple testing proce- Gregor A, Stephens R, Kristjansen P, Johnson B, dures for phase II trials. Mouse to man: statistical two-stage designs for phase II clinical trials. J Clin Res Drug Dev (1987) 1: selection and testing designs for comparative 21–30. Phase II trial design consid- assessment method: a practical design for phase I erations for small-cell lung cancer. Clinical trials designs for phase I clinical trials with late-onset toxicities. Phase II clinical patients required in a preliminary and a follow-up trial design for noncytotoxic anticancer agents for trial of a new chemotherapeutic agent. J Chronic which time to disease progression is the primary Dis (1961) 13: 346–53. Two-stage plans for patient accrual in discontinuation design: application to cytostatic phase II cancer clinical trials. Green  2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5 12 C ardiovascular LAWRENCE FRIEDMAN AND ELEANOR SCHRON National Heart, Lung, and Blood Institute, Bethesda, MD 20892 2482, USA INTRODUCTION public benefits, particularly if the treatment is simple and inexpensive, such as aspirin. Again Most of the principles in developing, managing because the condition is common, when there are and analysing clinical trials in cardiovascular potential treatments that are simple to administer, diseases are the same as for other conditions. Another important consideration is that athero- A major point that influences many of the clini- sclerotic and hypertensive cardiovascular dis- cal trials is that in developed countries, and unfor- eases are chronic conditions, often taking decades tunately more and more in developing nations, to develop and lasting many years after being cardiovascular disease is common. Clinical trials, therefore, may be sis and hypertension are the primary causes of initiated well before the development of risk fac- cardiovascular disease in adults, although there tors (sometimes called primordial prevention), are many contributing factors to these (often after the development of risk factors, but before termed risk factors). Although clinical trials have the occurrence of organ damage (primary pre- been conducted in other causes of cardiovas- vention), or after organ damage has occurred cular disease, including congenital conditions, (secondary prevention). There- potentially useful in all three settings, but others, fore, because in developed countries most heart particularly expensive or invasive approaches, disease, stroke and peripheral vascular diseases may be best suited for secondary prevention. Green  2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5 176 TEXTBOOK OF CLINICAL TRIALS level (though the latter has been clearly shown the body, such as the kidneys or the legs (as to affect recurrent infarctions and death). Rather, they may reduce the likeli- take various forms, such as angina pectoris, hood of having clinical sequelae or control the myocardial infarction, cardiac arrhythmias of serious consequences of disease. As noted, the common causes of cardiovas- the interventions studied in clinical trials may cular diseases (atherosclerosis and hypertension) be directed at any of those, though some are multifactorial in origin. Atherosclerosis may interventions, such as blood pressure lowering be influenced by cholesterol level, blood pres- drugs, may affect more than one outcome. As noted, interventions may affect influenced by things such as diet (intake of salt only one aspect of the disease. Therefore, inves- and various nutrients), obesity, physical activ- tigators would prefer to use as the outcome of ity, stress or emotion, and genetics. With regard interest only that most likely to be modified by to genetic influences, it is not thought that the the treatment. But for outcomes such as cause- common cardiovascular diseases or their risk fac- specific mortality, that is not easy. Rather, there broad outcome such as death due to cardiovascu- are likely to be many genes that interact with lar disease has limitations, because many deaths environmental conditions to effect most common are unwitnessed and autopsies much less common cardiovascular diseases. When finer splits are used, such risk factors, clinical trial interventions that alter as death due to arrhythmia or myocardial infarc- individual factors might yield only modest reduc- tion, the difficulties mount. On the other hand, treating hyper- as they convey considerable risk of death, even tension has led to only modest reductions in heart though they are asymptomatic. The multifac- conditions are common, there is rarely a short- torial nature of much cardiovascular disease has age of people with the condition of interest led some to design trials that have attempted to for most clinical trials. This can affect adherence to with surrogate endpoints on account of partici- study protocol and may lead to various drug pant unavailability. It is affecting the heart, as in coronary heart disease, still usually unnecessary to conduct trials with or the brain, as in stroke, but other parts of surrogate endpoints, but extra efforts do have CARDIOVASCULAR 177 to be made to identify and enroll the partic- TRIALS OF PHARMACOLOGIC AGENTS ipants. Connected with this, many physicians sub-specialise in particular types of cardiovas- Pharmaceutical agents are the most common cular disease. Involving the kind of physician interventions tested in clinical trials of cardio- most likely to have knowledge of and access vascular disease. Most trials of drugs are sim- to the relevant patient population is therefore ilar in structure and design to trials in any essential. A few points, how- the large size of many cardiovascular ever, should be made. Because, as noted above, clinical trials means that stratification to ensure most cardiovascular disease takes decades to balance among key baseline factors is usually develop, there is a long period when people unnecessary, with the notable exception of site, have few if any symptoms. Site is almost always a tence of atherosclerosis, for example, is usu- stratification variable. Beyond that, investigators ally determined by the presence of risk factors, should stratify on at most a very few variables. Because participants in age and sex; and for trials of blood pressure trials of primary prevention are asymptomatic, lowering, we would stratify by prior use of several principles apply. There- dramatic reduction in mortality from heart dis- fore, only drugs that are well-characterised (and ease and stroke over the past few decades in are presumably safe and well-tolerated) are gen- most developed countries. Second, the combination of improved prevention and much rate of clinical events is likely to be low. Unless better medical care, death rates in developed the trials use surrogate outcomes, they need to countries have decreased to a level that makes be very large (thousands and sometimes tens of mortality outcome studies less feasible. From a thousands of participants) and long (often five public health and a patient standpoint, this is years or more). Third, people who are asymp- certainly a happy state to be in, but it means tomatic and consequently notice no obvious ben- that clinical trials must be designed with the efit from treatment may have trouble adhering to expectation that the event rates may be consider- the regimen, especially in a long trial. Among the first large clinical trials in car- the remainder of this chapter will consider diovascular disease were trials of lipid lower- issues in specific trials. The Coronary Drug Project, which began of drugs or biologics, trials of devices and in the 1960s, tested five interventions (clofibrate, surgical procedures, and trials of lifestyle or nicotinic acid, dextrothyroxine, and two doses of other non-pharmacologic interventions. For fuller equine estrogen) against a placebo in men with a discussions of various cardiovascular disease history of a myocardial infarction. The interventions had major adverse 178 TEXTBOOK OF CLINICAL TRIALS events and three were stopped before the sched- reductions in all-cause mortality and in coronary uled end of the trial. Nicotinic acid was shown the intervention lowered low-density lipoprotein cholesterol by 35% and mortality by 30%. The Drug Project was that the mortality rate in the baseline serum cholesterol level was somewhat control group was only two-thirds of that pre- lower in this trial than in the 4S trial. This proba- 4S, there was greater than a 30% reduction in bly reflected selection of better risk participants, low-density lipoprotein cholesterol and a 24% but improved care may also have played a role. The next large lipid-lowering trial was the As a result of these and other trials of choles- Lipid Research Clinics Coronary Primary Preven- 10 terol lowering and trials of blood pressure reduc- tion Trial. This trial compared cholestryramine tion, new evidence-based guidelines for treatment resin versus placebo to see if there would be a dif- of risk factors such as hyperlipidaemia and hyper- ference in the primary outcome of coronary heart tension have been developed and widely dissem- disease death or non-fatal myocardial infarction inated. Therefore, regardless of whether the trial in 3806 men free of prior evidence of heart is one of primary prevention or in people with disease, but with hyperlipoproteinaemia.

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