Pravastatin clinical trials

Dinnett EM, Mungall MMB, Kent JA, Ronald ES, Gaw A. Closing out a large clinical trial lessons from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Clin Trials 2004 1.6 545-52. 

As indicated in Table 1, statins, which block cholesterol biosynthesis by inhibition of hepatic HMGCoA reductase, have been used extensively to reduce LDL-C levels. At most therapeutic doses, statins marginally increase HDL levels by 5-10% [3,16]. The HDL elevation observed with statins has been highly variable and not easily extrapolated from the effects on LDL. A recent study (STELLAR) demonstrated increased HDL elevation with the use of rosuvastatin compared to simvastatin, pravastatin or atorvastatin (10% vs. 2-6%) [16,24], Although the mechanism of HDL elevation by statins is not clearly understood, it is proposed that statins enhance hepatic apoA-I synthesis [25] and decrease apoB-containing lipoproteins [26]. A number of clinical trials have demonstrated that statins reduce the risk of major coronary events. However, it is not clear if the statin-induced rise in HDL levels is an independent contributor to the reduced risk of coronary events. The observed small increase in HDL and adverse side effect profile related to liver function abnormalities and muscle toxicity limits the use of statins as monotherapy for HDL elevation [27],... 

Clinical trials with lovastatin (Mevacor), simvastatin (Zocor) and pravastatin (Pravachol) provided much of the evidence supporting the observation that lowering... 

Although myopathy is rarely seen with pravastatin in clinical trials, it does occur. 

Newman TJ, Kassler-Taub KB, Gelarden RT, et al. Safety of pravastatin in long-term clinical trials conducted in the united states. J Drug Dev 1990 3 275-80. 

Recent reports on clinical trials of pravastatin and simvastatin have shown a significant reduction in patient mortality rates for both hypercholesterolemic patients without known coronary heart disease and for those with existing coronary heart disease [7,8], These trials have established cholesterol-lowering agents as an effective treatment for coronary disease and have stimulated the search for new cholesterol-lowering agents with other mechanisms of action. 

Meanwhile, the industry s R D race produced additional HMG-CoA reductase agents. Sankyo s second HMG-CoA reductase inhibitor, pravastatin, licensed to Bristol-Myers Squibb, entered phase III clinical trials in Japan at the same time lovastatin entered phase III clinical trials in the United States. In October 1990, 21 months after Bristol-Myers Squibb submitted the NDA on January 31, 1989, FDA s Endocrinologic and Metabolic Advisory Committee unanimously recommended pravastatin be approved On October 31, 1991, 3 years after approval in Japan, the FDA approved pravastatin with a 1C rating, a new molecular entity (NME) with little or no therapeutic gain over existing therapies. Bristol-Myers Squibb initially offered pravastatin at a direct price discount of 5 percent and a 10 percent discount to wholesalers of lovastatin. By 1993, pravastatin s sales are estimated to reach 500 million. 

In addition to these newer agents, there are currently three fibrate-based combinations with HMG-CoA reductase inhibitors in clinical trials. In phase III, Sciele has fenofibrate/pravastatin combination and AstraZeneca and Abbott have rosuvastatin/choline fenofibrate (ABT335), while in phase II, Life Cycle Pharma have atorvastatin / fenofibrate. 

Multiple well-controlled clinical trials have documented the efficacy and safety of simvastatin, pravastatin, lovastatin, and atorvastatin in reducing fatal and nonfatal CHD events, strokes, and total mortality. Rates of adverse events in statin trials were the same in the placebo groups and in the groups receiving the drug. This was true with regard to noncardiac illness and the two laboratory tests, hepatic transaminases and creatine kinase (CK), that are commonly monitored in patients taking statins. 

In 1981, pravastatin was chosen for development as a hypolipidemic drug, and clinical trials began in 1984. Pravastatin was approved for production in 1989 and launched in the same year as "Mevalotin" in Japan. The drug was licensed to Bristol-Myers Squibb Company and has been developed worldwide. Pravastatin has already been sold commercially in 47 countries including Japan. 

In high-risk individuals and groups people with clinical evidence of macrovascular disease other than CHD, the Heart Protection Study (HPS) (II) with diabetes, the HPS and Collaborative Atorvastatin Diabetes Study (CARDS) (12) the elderly, Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) (13) or with hypertension, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (14) and Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) (15). 

Clinical efficacy of anti-inflammatory properties has been shown in several trials independent of their lipid-lowering effects (18,19). Statins reduce CRP levels and it is known that elevated CRP levels are associated with restenosis. Counter intuitively, however, several trials tested statins for restenosis prevention and were disappointing (20-23). The only trial that showed reduction in restenosis was the REGRESS trial (24), which used pravastatin 40 mg once daily for a period of two years. In this study, the binary restenosis assessed at two... 

More controversial is the extent to which primary prevention (treatment of clinically unaffected patients with moderate elevation of cholesterol levels) should include drugs, and whether secondary prevention should ever start with drugs rather than diet. Dietary treatment can lower cholesterol levels in committed subjects, and is obviously less costly than drug treatment. Unforhmately numerous studies have shown that over any substantial period of time (e.g. one year) diet has no clinically significant influence on plasma cholesterol and the wait for diet to have an effect often results in patients being lost from hospital follow-up after their initial myocardial infarction. Evidence comes from the WOSCOPS stud) in which pravastatin 40 mg/day and placebo were compared in 6590 men age 50-70 with LDL cholesterol 4-6 mmol/1 pravastatin reduced coronary heart disease (fatal and nonfatal events) by 31%. The authors estimated that treatment of 1000 such subjects each year would prevent 20 myocardial infarctions. Concerns that primary prevention could have a net adverse outcome (that cholesterol reduction increased the risk of cancer or violent deaths) have been laid to rest by a number of outcome trials. 

With the advent of the statin class of drugs, lowering of low density lipoprotein (LDL) cholesterol to a meaningful degree became clinically achievable in most patients with vascular disease. There have been three large trials of statins in secondary prevention of MI (61) the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study, the Cholesterol and Recurrent Events (CARE) study, and the Scandinavian... 

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