Pravastatin trial

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. 

Tseng MY, Czosnyka M, Richards H, Pickard JD, Kirkpatrick PJ. Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage a phase II randomized placebo-controlled trial. Stroke 2005 36 1627-1632. 

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],... 

Shepherd, J., Blauw, G.J., Murphy, M.B., et al. (2002) PROSPER Study Group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER) a randomized controlled trial. Lancet, 360, 1623-1630. 

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

HMG CoA reductase inhibitors can be associated with small rises in alanine transaminase activity, but have not been definitely associated with severe morbidity involving altered hepatic function. The results of randomized trials do not suggest that statins in standard doses are hepato-toxic. In none of the large randomized studies in which standard doses were assessed (atorvastatin 10 mg/day, fluvastatin 40-80 mg/day, pravastatin 40 mg/day, simvastatin 20-40 mg/day) was there any clear excess risk of hepatitis or any other serious liver-related adverse events. Long-term large randomized trials have confirmed an excess of persistent rises in transaminases with atorvastatin 80 mg/day compared with lower doses or placebo, and similarly some excess with simvastatin 80 mg/day, but hepatitis and liver failure were not reported (4). 

Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996 335(14) 1001-9. 

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. 

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). 

The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002 288 2998-3007. 

Thompson PL, Meredith I, AmerenaJ, Campbell TJ, Sloman JG, Harris PJ. Effect of pravastatin compared with placebo initiated within 24 hours of onset of acute myocardial infarction or unstable angina the Pravastatin in Acute Coronary Treatment (PACT) trial. Am Heart J 2004 I48 e2. 

Ridker PM, Morrow DA, Rose LM, Rifai N, Cannon CR Braunwald E, Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol >70mg/dl and C-reactive protein >2mg/l an analysis of the PROVE-IT TIMI-22 trial. J Am Coll Cardiol 2005 45 1644-1648. 

Bertrand ME, McFadden EP Fruchart JC, et al. Effect of pravastatin on angiographic restenosis after coronary balloon angioplasty. The PREDICT Trial Investigators. Prevention of Restenosis by Elisor after Transluminal Coronary Angioplasty. J Am Coll Cardiol 1997 30 863-869. 

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... 

I 9 Albert MA, Danielson E, Rifai N, et al, Effect of statin therapy on C-reactive protein levels the pravastatin inflammation/CRP evaluation (PRINCE). A randomized trial and cohort study, JAMA 2001 286 64-70. 

Mulder HJ, Bal ET, Jukema JW, et al. Pravastatin reduces restenosis two years after percutaneous transluminal coronary angioplasty (REGRESS trial). Am J Cardiol 2000 86 742-746,... 

In contrast to Ato Z trial, the CRP levels fell from a median of 12,3 mg/L at baseline to 2,1 mg/L in the pravastatin group and 1,3 mg in the atorvastatin group in the PROVE-IT TIMI 22 trial (36), The primary end point of all caused death, myocardial infarction, and unstable angina requiring hospitalization was 26.3% in the pravastatin and 22.4% in the atorvastatin group. This represents a 16% reduction in the hazard ratio, favoring atorvastatin. 

Today HMG-CoA reductase inhibitors (statins) account for the large majority of prescriptions for lipid-lowering drugs in most countries. As discussed in a subsequent section of this chapter, the widespread acceptance of this drug class is due not only to excellent efficacy and tolerability but also to the publication of several very large intervention trials, which have unequivocally demonstrated the effectiveness of the first three members of the class—lovastatin, simvastatin, and pravastatin—in reducing coronary morbidity and mortality. 

The purpose of altering plasma lipoprotein levels is to reduce the risk of coronary events. The results of outcome trials are available for lovastatin (Downs et al, 1998), simvastatin (Scandinavian Simvastatin Survival Study Group 1994), and pravastatin (Shepherd et al, 1995 Sacks et al, 1996 The Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID) Study Group, 1998). Three of these trials, 4S, Cholesterol and Recurrent Events (CARE), and LIPID, studied patients with CHD, whereas the West of Scotland Coronary Revention Study Group and the Air Force Coronary Atherosclesosis Prevention Study (AFCAPS) evaluated the benefits of therapy in patients without known CHD. The main results of these trials are summarized in Tables la and lb. 

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