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News 07/05/2544


STATUS OF STATINS: INDICATIONS, UTILIZATION, AND UNANSWERED QUESTIONS
The use of HMG-CoA reductase inhibitors is expanding, and even after extensive use, statins have left some questions unanswered.

HEPARIN-INDUCED THROMBOCYTOPENIA CAN OCCUR RAPIDLY AFTER PRIOR HEPARIN USE
Thrombocytopenia resulting from heparin administration can begin rapidly among patients who have received heparin within the previous 100 days.

TERMINALLY ILL PATIENTS IN PAIN OFTEN SHUN MEDICATION
The presence of moderate to severe pain in terminally ill patients may not be due so much to undertreatment as it is to patients' fear of addiction and their distaste for opioid side effects.


Status of Statins: Indications, Utilization, and Unanswered Questions

Samir Malhotra, MD, DM, Anil Grover, MD, DM, G. Munjal, MD


Abstract

Several landmark trials have established statins as first-line lipid-lowering therapy for the secondary prevention of coronary artery disease (CAD). Recent evidence has supported their role in primary prevention of CAD as well. Their range of indications seems to be expanding, and patients with diabetes mellitus, acute coronary syndromes (ACS), and dyslipidemias associated with uremia may also benefit from statins. Emerging data suggest that the statins also possess immunosuppressive, antiproliferative, and blood pressure lowering effects. Despite overwhelming proof of efficacy and safety, statins seem to be underused, especially in the geriatric age group. Even after extensive use, statins have left some questions unanswered, like which of them is a better choice, up to what levels should low density lipoprotein cholesterol (LDL-C) be lowered, what is their effect on fibrinogen and apolipoprotein (B) levels, and what is their role in dyslipidemias associated with HIV infection. Although earlier concerns with regard to risk of cancer, cataracts, and CNS toxicity have not been substantiated, concerns have recently arisen with regard to risk of peripheral neuropathy.

Introduction

Coronary artery disease (CAD) is a leading cause of morbidity and mortality in the developed,[1] as well as developing, countries.[2] It is well established that patients with dyslipidemias are at an increased risk of developing atherosclerosis and subsequent CAD. The availability of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins") has revolutionized the treatment of lipid abnormalities. Not surprisingly, the decade of the 1990s has been termed the "statin decennial" in the history of CAD prevention.[3] The developments in this field are taking place at a rapid rate, and it is difficult to keep pace with them. This review summarizes the current indications for statins, highlights their use patterns, and reflects on some issues that are not resolved.

Indications for Statins

Primary Prevention of CAD

The effectiveness of drug treatment for lipid disorders in patients with no history of CAD has been controversial.[4-6] Earlier reviews cautioned against drug treatment in patients with low to moderate risk of death from CAD because of possible increases in all-cause mortality with treatment.[7] A more recent meta-analysis found that CAD events and all-cause mortality were reduced in primary prevention populations.[8]

The latest large primary prevention trial to be published is the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/Tex CAPS).[9] More than 6000 patients (with average total cholesterol 150 mg/dL) were followed up for more than 5 years after lovastatin treatment. Low-density lipoprotein cholesterol (LDL-C) levels decreased by 25% and high-density lipoprotein-cholesterol (HDL-C) levels increased by 6%. This study concluded that, for every 100 men and women treated with lovastatin, 19 major coronary events, 12 myocardial infarctions (MIs), and 17 coronary revascularizations could be prevented.

The confirmation that lipid lowering reduces CAD mortality when used as primary prevention intervention came from a recent meta-analysis.[10] Using data from 4 randomized trials,[11-14] it was concluded that drug treatment reduced the odds of a CAD event by 30% (odds ratio [OR] 0.70, 95% confidence interval [CI] 0.62-0.79). However, the odds of all-cause mortality were not reduced (OR 0.94, 95% CI 0.81-1.09). Although 2 of the 4 trials did not use statins, even when statins were considered alone, there were no substantial differences in all-cause mortality.

The fact that statins reduce CAD-related events but not all-cause mortality raises a pertinent question: Does drug treatment increase mortality from non-CAD-related causes? There cannot be a straightforward "yes" or "no" to this question because the absolute risk of all-cause mortality in primary prevention patients is relatively low (2% to 4% over 5 years in these trials). Therefore, the absolute benefit in lives saved will also be initially low and the number needed to treat (NNT) is very high. Moreover, preventing nonfatal events may also improve all-cause mortality over a longer span than the 5-7 years observed in these trials, but data about the magnitude of that effect are not currently available.[10]

Secondary Prevention of CAD

Several randomized trials using statins have also demonstrated a benefit in the secondary prevention of CAD, both in terms of retardation of the progression of signs of coronary atherosclerosis and reduced morbidity and mortality rates. Three of these "landmark trials" have examined the long-term effect of statins in patients with previous MI. The Scandinavian Simvastatin Survival Study (4S),[15] the Cholesterol And Recurrent Events (CARE) trial,[16] and the Long Term Intervention with Pravastatin in Ischemic Disease (LIPID) study[17] have shown that a reduction in LDL-C levels of about 25% to 35% leads to a reduction in CAD events of about 24% to 42%.

The question that is being debated today is: How low is low enough? The National Cholesterol Education Programme (NCEP) guidelines suggest desirable LDL-C levels of less than 130 mg/dL.[18] However, more than half of the patients with CAD have cholesterol levels that are below the desirable range of NCEP guidelines.[19] Moreover, in epidemiologic studies, there is no cut-off point below which there is no risk of CAD; rather, there is continuously increasing risk with increasing cholesterol levels.[20] This gave rise to the concept of "aggressive lipid lowering," which was also supported by the results of the 4S trial,[15] subset analysis of the Cholesterol Lowering Atherosclerosis study (CLAS),[21] and the Regression Growth Evaluation Statin Study (REGRESS).[22]

The 2 pravastatin trials, CARE[16] and LIPID,[17] contradict this concept and conclude that there is no additional benefit of reducing LDL-C below 125 mg/dL. A meta-analysis published in 1997 also concluded that there is no benefit in decreasing baseline LDL-C levels by more than 20%.[23] The issue is further made confusing by evidence from the Post Coronary Artery Bypass Graft[24] and the Atorvastatin VErsus Revascularization Treatment (AVERT)[25] trials. The first of these showed that aggressive lipid lowering (LDL-C < 100 mg/dL) was superior to moderate lipid lowering (LDL-C < 134 mg/dL). The AVERT trial compared aggressive lipid lowering (LDL-C < 115 mg/dL) with atorvastatin and resulted in a lower percentage of grafts showing progression of arteriosclerosis (27% vs 39%, P < .001) and a lower rate of revascularization (6.5% vs 9.2%, P = .03).[24] The AVERT trial compared aggressive lipid lowering with atorvastatin (80 mg/day) vs angioplasty and showed that fewer patients reached the end point (death, MI, stroke, revascularization, and hospitalization for worsening angina) in the atorvastatin group (13% vs 21% for angioplasty. The atorvastatin group had a lower rate of bypass surgery (1.2% vs 5.1%) and hospitalization for worsening angina (6.7% vs 14.1%). The time to the first ischemic event was significantly longer in the atorvastatin group compared with the placebo group.

Although some experts recommend that the most important and only goal of therapy with statins is to reduce the LDL-C levels by 20% to 30%,[26,27] we believe that such a conclusion may not actually reflect actual practice, and further evidence is required to unequivocally answer this question.

Acute Coronary Syndromes

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study[28] was designed to determine whether early, rapid, and profound cholesterol lowering with atorvastatin can reduce early recurrent ischemic events in patients with unstable angina or non-Q-wave acute MI. The results show that atorvastatin 80 mg daily, starting within the first 24 to 76 hours after an acute coronary event and maintained for 4 months, improves the cardiovascular prognosis by decreasing the combined risk of death (any cause) nonfatal MI, resuscitated cardiac arrest, and worsening angina with new objective evidence of ischemia requiring urgent hospitalization.[29]

The management of unstable angina/non-Q-wave MI has undergone dramatic changes over the past few years, and it appears that statin therapy is an altogether novel approach that will add a new dimension to therapy. As part of combination therapy that includes anti-ischemic therapy, aspirin, low-molecular weight heparin, and now a high dose of statins, the ACS invasive attitude must be guided by the electrical, biological, and prognostic risk.[30]

Diabetes Mellitus

Atherosclerosis is more extensive and occurs earlier in patients with diabetes than in the general population. Not surprisingly, CAD, stroke, and MI (also silent MI) occur with increased frequency in patients with diabetes.[31] A post hoc subset analysis of data from 202 patients with diabetes and 4242 nondiabetic patients from the 4S trial showed that the absolute clinical benefit achieved by cholesterol lowering may be greater in diabetic than in nondiabetic patients with CAD.[32]

Grover and colleagues[33] estimated the long-term costs and benefits of treating hyperlipidemia among patients with and without known cardiovascular disease after validating the Cardiovascular Life Expectancy Model. In this model, the authors performed simulations for diabetic patients with and without known cardiovascular disease who were 40 to 70 years of age. The long-term risk of CVS events was forecasted, and the need for medical and surgical intervention and the associated costs in US dollars were assessed. The model validated well against the observed results of the 4S trial. In validation, the model estimates fell within the 95% confidence intervals of the observed results for end points. The results suggest substantial benefits of primary prevention in patients with diabetes without cardiovascular disease. The conclusions were robust even among diabetics with lower baseline LDL-C values and smaller LDL-C reductions. These data have come from post hoc subgroup analyses. Two ongoing trials, the Collaborative Atorvastatin Diabetes Study (CARDS) and Lipids in Diabetes Study (LDS), should provide us with sufficient information to further support the role of statins in the management of diabetes and resulting CAD.[34] CARDS and LDS are early-stage primary prevention trials with clinical events as the primary end points; recruitment is still ongoing. Pharmacotherapy in the CARDS trial included atorvastatin. The LDS study used cerivastatin either alone or in combination with micronized fenofibrate.

Dyslipidemia of Uremia

The effects of atorvastatin on dyslipidemia in uremic patients who were on peritoneal dialysis were studied.[35] Patients were treated for 4 months with atorvastatin at a starting dose of 10 mg. The dose could be increased to 20 or 40 mg in order to achieve an LDL-C of less than 130 mg/dL for primary prevention of CAD, an LDL-C of less than 100 mg/dL for secondary prevention, and plasma triglycerides of less than 200 mg/dL. The study showed beneficial effects of atorvastatin in this setting. However, the number of patients was small (n = 31), and more evidence is needed before a definite conclusion can be reached.

Non-Lipid-Lowering Uses of Statins

The beneficial effects of statins in ACS may be related to a protective effect on endothelial dysfunction, stabilization of plaque, and modification of the coagulation pathway.[35] Antiproliferative and immunosuppressive actions have been attributed to statins.[36] These effects need to be confirmed in controlled clinical trials and specifically in transplant rejection. Statins also seem to possess a blood pressure lowering effect that may be clinically relevant.[37] The immunosuppressive action of statins includes modulation of T-cell activation, an effect that can provide scientific rationale for using statins as immunosuppressants during organ transplantation.

Utilization Patterns of Statins

Interesting trends have emerged from utilization studies of statins. Although most studies have reported underutilization, there has also been evidence of overutilization. Overuse of statin therapy was found among 69% of patients undergoing primary prevention in a recent study.[38] The same study reported that among patients with CAD who were not taking statins, 88% were undertreated.

A number of studies from Europe[39] and the United States[40,41] have reported underutilization of statins. Our own studies have similarly reported underutilization in the cardiology outpatient department[42] as well as in the hypertension clinic[43] of a tertiary care hospital. Not only are lipid-lowering drugs underused, but they may not be used long enough to observe a benefit,[44] or they may be used at doses lower than the established defined daily doses.[45] Or, the therapy may not be directed at the population likely to benefit most.[46] And although the use of statins has increased about 4-fold over the past few years,[42-45] they are still underused. Moreover, patients aged 75 years and over with CAD are unlikely to be prescribed statins[47] despite the evidence that such use is justified.[48] The authors concluded that the reason for underuse was poorly explained by the measures of health needed.

Therefore, aggressive measures are required to improve utilization and adherence of these drugs through improved physician and patient education along with appropriate patient selection.[49]

Pharmacoeconomics of Statin Use

Earlier cholesterol reduction cost-effectiveness studies with nonstatin treatments (bile acid resins, fibrates, niacin) suggested that only patients at extremely high risk could be treated with lipid therapy in a cost-effective manner.[50] Recent outcomes data, however, demonstrate that statins have a broadly favorable cost-effectiveness profile both for primary as well as secondary prevention of CAD.[50]

A comparison of cost-effectiveness of different statins in the 4S study showed that cost per year of life saved ranged from $5421 with atorvastatin to $15,073 with lovastatin.[51] A post hoc pharmacoeconomic analysis[52] of a multicenter, randomized trial[53] that included 5 statins -- atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin -- showed that the annual acquisition cost/percentage LDL-C reduction was lowest with atorvastatin 10 mg ($17.96), fluvastatin 40 mg ($19.83), atorvastatin 20 mg ($22.85), and atorvastatin 20 mg ($24.96). A population-based treat-to-target analysis, based on a meta-analysis (76 trials included), showed that atorvastatin was the most cost-effective agent, followed by fluvastatin.[54] The authors recommended that atorvastatin and fluvastatin should be available on formularies.

Which Statin to Use?

A comparative dose efficacy study of 5 statins demonstrated that atorvastatin 10, 20, and 40 mg produced greater (P <= .01) reductions in LDL-C -- 38%, 46%, and 51%, respectively -- than the milligram equivalent doses of simvastatin, pravastatin, lovastatin, and fluvastatin.[52] Another multicenter, randomized, treat-to-target study that compared 4 statins (atorvastatin, fluvastatin, lovastatin, and simvastatin) showed that at the starting dose, atorvastatin decreased LDL-C levels significantly (P < .05) compared with other statins, and the percentage of patients reaching target LDL-C concentrations was significantly greater in the atorvastatin group.[55]

Another comparison of simvastatin (20, 40 mg) and atorvastatin (10, 20 mg) given for 6 weeks showed that both drugs produced similar changes in LDL-C (ranging from 35% to 42%) and achieved an LDL-C level of 130 mg/dL or lower in a similar number of patients.[56]

The question of how low LDL-C levels should be lowered has not been clearly answered, and there is evidence for both aggressive lipid lowering (LDL-C < 100 mg/dL) or a more guided 20% to 30% lowering of LDL-C. The use of more potent statins such as atorvastatin and simvastatin, which affords greater lowering of LDL-C and triglyceride levels and allows more patients to achieve LDL-C goals, should be considered.[57] However, since other statins have shown similar reductions in mortality and other CAD-related events, they may also be substituted. This may be due to the stabilization of plaque by statins, which affords significant clinical benefits and prevents clinical symptoms. A 20% to 30% reduction of LDL-C levels may be sufficient to stabilize the plaque.

Safety Concerns

All statins seem to share the adverse-effect profile of this class[53,55,56] with a less than 2%[58] incidence of undesirable effects, such as an increase in hepatic transaminases, increased creatine phosphokinase levels, and myositis. The initial concerns with regard to the risk of cancer, cataracts, and CNS toxicity, have not been substantiated.[59-61] There seems to be some risk of peripheral neuropathy; several cases have been reported.[62] The predisposing factors for the development of peripheral neuropathy have not been clearly identified and the neuropathy appears to be reversible. All statins have been implicated, and this appears to be a class effect.

Areas of interest include the effect of statins on fibrinogen and apolipoprotein B levels, the status in dyslipidemias of HIV infection, and the effect on blood pressure and immunity. That statins are safe and efficacious seems to be a foregone conclusion, but the challenge seems to be to fully implement these benefits across the wide spectrum of the at-risk population.[63] Ongoing trials may provide answers to some or all of the questions that are at present unanswered.

Conclusion

Statins are a useful class of drugs. However, a number of issues are unresolved. For example, should LDL-C be aggressively lowered or not? Should statins be used in primary or secondary prevention or both? Are they being underused or overused? Are their non-lipid-lowering effects of major clinical significance?

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Heparin-Induced Thrombocytopenia Can Occur Rapidly After Prior Heparin Use


WESTPORT, CT (Reuters Health) Apr 26 - Thrombocytopenia resulting from heparin administration can begin rapidly among patients who have received heparin within the previous 100 days, according to a report in the April 26th issue of the New England Journal of Medicine.

Dr. Theodore E. Warkentin from the Hamilton Health Sciences Corporation and Dr. John G. Kelton from McMaster University in Hamilton, Ontario, Canada analyzed the time from the start of heparin therapy to the start of thrombocytopenia among 243 patients with heparin-induced thrombocytopenia.

In 70% of the patients a decrease in platelet count began at 4 or more days after the start of heparin therapy. Among these patients, previous heparin therapy appeared to have no influence on when thrombocytopenia began, the researchers report.

However, the onset of thrombocytopenia was rapid among the remaining 30% of the patients, all of whom had prior heparin treatment within the preceding 100 days. The median time to onset of thrombocytopenia in these patients was 10.5 hours after heparin administration, Drs. Warkentin and Kelton found.

Using a test for antibodies against platelet factor 4, the researchers also studied the presence of heparin-dependent antibodies in these patients. In addition, they looked at the outcome of seven patients who had had a previous episode of heparin-induced thrombocytopenia, and were given heparin therapy again.

Depending on the assay performed, heparin-dependent antibodies decreased to undetectable levels at a median of 50 to 85 days as patients recovered from their episode of thrombocytopenia, the researchers note.

Furthermore, there were no further incidents of heparin-induced thrombocytopenia among the seven patients who received heparin again after heparin-dependent antibodies had disappeared.

"We believe," Drs. Warkentin and Kelton write "that the use of heparin in patients with a history of heparin-induced thrombocytopenia should be restricted to patients with a compelling indication for its use...and that it should be considered only if heparin-dependent antibodies cannot be detected by a sensitive assay."

N Engl J Med 2001;344:1286-1292.


Terminally Ill Patients in Pain Often Shun Medication


LONDON (Reuters Health) Apr 26 - The presence of moderate to severe pain in terminally ill patients may not be due so much to undertreatment as it is to patients' fear of addiction and their distaste for opioid side effects, according to Dr. Ezekiel J. Emanuel, of the National Institutes of Health, Bethesda, Maryland, and associates.

Dr. Emanuel's group interviewed 988 patients with predicted survival of less than 6 months. Patients were evenly divided in terms of reporting severe, moderate, minimal, and no pain. Pain was as prevalent among patients with nonmalignant illnesses as in patients with cancer.

Fewer than a third of those with moderate or severe pain reported a desire to increase pain treatment, the investigators report in the April 28th issue of The Lancet. Approximately 1 patient in 10 who was experiencing pain had reduced or stopped taking treatment altogether. Reasons for not wanting additional pain therapy included constipation and mental confusion, as well as potential addiction.

"It seems that the patients in [this] study were collectively ill-informed about pain, prejudiced possibly by bad experiences, and inadequately cared for by their physicians," Dr. Sam Hjelmeland Ahmedzai, of the University of Sheffield in the UK, writes in an accompanying commentary.

Dr. Ahmedzai notes that substituting drugs such as fentanyl for morphine can reduce problems with tolerance and constipation. Adding psychostimulants or subanalgesic doses of oxycodone to morphine can increase pain relief and reduce mental side effects, he adds. He also points out that many other means of pain relief, such as nerve blocks, cognitive behavioral therapy, and intrathecal drug administration, are available to clinicians.

Lancet 2001;357:1311-1315,1304-1305.


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