Q1. Pharmacotherapy: Monotherapy

objective

There is good evidence supporting lipid-lowering therapy for primary and secondary prevention of CVD, based on LDL-C and CVD risk.  Patients with known CVD or multiple risk factors require more aggressive treatment.

 

background

NCEP ATP-III identifies the landmark trials that continue to support the benefits of aggressive therapy with statins to reduce lipid levels for both primary and secondary prevention.  An update to this report (Grundy et al., 2004) reviews the clinical trials on current and novel therapies that emphasize the importance of intensifying lipid-lowering treatment to improve outcomes.  It further highlights the current gap in CHD treatment that exists in hospital and outpatient settings; recognizes the significant number of eligible patients not receiving therapy; and correlates this with the significant opportunity for reduced morbidity and mortality with proper treatment.

NCEP ATP-III emphasizes that aggressive drug therapy may slow, stabilize, and cause regression of plaque growth, and notes that an emerging body of evidence suggests that statin therapy has a salutary benefit for raising HDL-C and lowering LDL-C to synergistically reduce CHD risk.  ATP-III also reviews the anti-inflammatory and pleiotropic effects of statins, and their benefits beyond LDL-C reduction in reducing CHD risk, and emphasizes the increasing importance and clinical relevance of the measurement of non-HDL-C and inflammatory markers in evaluating and treating CHD risk.  Since LDL-C is the primary target of therapy in the primary and secondary prevention of CVD, statins are the first line therapy for most patients.  Statins have the advantage of potency, ease of use, and tolerability over other cholesterol lowering agents.
Table 6 summarizes the recommended choice of drugs for dyslipidemia.

recommendations

1. Pharmacologic treatment of dyslipidemia should be individualized and dictated by lipid levels.  [B]

Elevated LDL-C

2. Statins are first line agents in primary and secondary prevention of CVD regardless of HDL-C or TG level.  [A]
3. Moderate doses of formulary statins (to achieve an LDL-C reduction of 25 percent or greater) should be initiated unless a patient is considered to be at greater than usual risk for adverse events from statins (e.g., myopathy).  [A]
4. For patients who cannot tolerate statins, niacin or resins should be considered for treatment.  [A]
5. There is insufficient clinical outcome evidence to recommend ezetimibe monotherapy for reduction of CV risk.  [I]
6. Ezetimibe can be considered for lowering LDL-C in patients who are unable to tolerate other lipid-lowering drugs.  [A]
7. The dose of statin should be adjusted at 6 to 12 week intervals until individual LDL-C goals are achieved or statin doses have been maximized.  [I]

Isolated Hypertriglyceridemia

8. Niacin, fibrates, or fish oil supplements may be used in treatment of hypertriglyceridemia.  [B]

Isolated Low HDL-C

9. For secondary prevention, gemfibrozil or niacin may be used in patients with isolated low HDL-C and normal LDL-C.  [A-Gemfibrozil; B-Niacin]

Safety and Follow-Up

10. Patients treated with statins or fibrates should be educated regarding the importance of recognizing and reporting any unexplained muscle tenderness, pain, or weakness.  [I]
11. Lipid profiles should be repeated 6-12 weeks after initiation of therapy and/or change in dose and/or combination therapy.  [B]
12. Liver function tests (LFTs) should be performed prior to and after 12 weeks following initiation of treatment, any elevation in dose, and periodically thereafter in those receiving statins, fibrates, or niacin.  [I]
13. Creatine kinase (CK) levels should be obtained in patients who develop muscle pain, weakness, or tenderness after institution of statin or fibrate therapy.  [I]

discussion

There are a large number of clinical trials evaluating pharmacotherapy of dyslipidemia.  These trials can be separated into several categories: lipid lowering studies, primary prevention trials, and secondary preventions.  The prevention trials can be further divided into trials that examine hard clinical outcomes (such as death, MI, and other CV events) and studies that have intermediate outcomes (such as angiographic studies).  This guideline gives priority to studies with hard clinical outcomes.  A detailed discussion of the important clinical trials for primary and secondary prevention can be found in Appendix F.

Pharmacotherapy for Primary and Secondary Prevention (Monotherapy)

It should be emphasized that all clinical trials demonstrating beneficial clinical outcomes with statins have utilized doses that result in a LDL-C lowering of at least 25 percent (see Appendix F).  In order to achieve LDL-C lowering of this magnitude, moderate doses of statins are usually required (See Table 7).  Since none of these trials used a target LDL-C to guide dose of statin, the emphasis on treatment of dyslipidemia for primary prevention should focus on providing a statin to lower LDL-C at least 25 percent.

Furthermore, no primary prevention trial has demonstrated lowering of clinical outcomes in patients at low 10-year risk for events. Thus, there is insufficient evidence to recommend pharmacotherapy in low-risk patients, although prudence would suggest following NCEP (2002) recommendations for those individuals with very high LDL-C levels.

Primary Prevention

Lipid-lowering treatment has been shown to reduce CHD events, cardiovascular mortality, and total mortality in patients without known CHD, although these trials have focused on patient populations with significant 10-year risk for events.

Treatment should be based on risk, which varies widely in this group of patients.  Drug therapy is indicated for the primary prevention of CVD in patients at moderate to high-risk for CHD who remain above LDL-C thresholds with non-pharmacologic measures.

Secondary Prevention

Lipid-lowering treatment has been shown to reduce CHD events, CV mortality, and total mortality in patients with CHD.

Patients with CHD or CVD or those with diabetes should have statins initiated when LDL-C level remains above 130 mg/dL despite diet and exercise.

Special Populations

White males have been studied most frequently in clinical trials for the prevention of CAD.  However, there is evidence that women, non-whites, and elderly patients all benefit from lipid lowering therapy based on the presence of other risk factors.  Women have been included in most lipid lowering trials, albeit in small numbers for some studies.  A meta-analysis of clinical trials found a significant reduction in CHD events in women and the elderly similar to the reductions observed with men and those younger than 65 years of age (LaRosa et al., 1999). A second, more recent meta-analysis of clinical trials of women treated with lipid-lowering drugs did not find a statistical difference in CHD events in women without known CHD but did find a significant reduction in CHD events in women with known CHD (Walsh & Pignone, 2004).  However, the authors comment that some of the analyses were limited because of the low number of CHD events in the available trials. Some larger clinical trials had adequate numbers of women enrolled to demonstrate a decrease in clinical outcomes (CARE, 1996; 4S, 1994; HPS, 2002; PROVE-IT, 2004), while other trials did not show statistically significant benefit (LIPID, 1998; AFCAPS/TexCAPS, 1998; ASCOT-LLA, 2003; A to Z, 2004) likely related to inadequate statistical power. Older age patients also benefit from lipid-lowering therapy, based on risk factors.  Nearly all the clinical trials have shown benefit in patients older than 60-65 years of age (4S, 1994; CARE, 1996; LIPID, 1998; WOSCOPS, 1995; ASCOT-LLA, 2003; etc).  Indeed, in HPS and PROSPER, there was clinical benefit observed in patients age 70 and above.

Although African Americans have high rates of CHD mortality, they are significantly under-represented in most dyslipidemia clinical trials.  Most large clinical trials do not report non-white race as a demographic feature; of the few studies that list race, results of benefit based on race are not reported.  We are unaware of any meta-analysis or study that has demonstrated benefits of lipid-lowering therapy in non-white patients.  However, although not based on evidence, we concur with the recommendations of ATP-III that non-white patients should obtain similar treatment for dyslipidemia, based on risk factor assessment.

STATINS

Primary Prevention

The 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitors, also known as statins, are considered first line agents in most cases because of their effectiveness in reducing LDL-C, their safety and tolerability, and because of their demonstrated ability to reduce CV morbidity and mortality in clinical primary prevention trials (WOSCOPS-Shepherd, 1995; AFCAPs/TexCAPS-Downs et al., 1998; ASCOT-LLA-Sever, 2003). Only statins have been demonstrated to lower mortality for primary prevention. Other agents have been shown to reduce major CHD events (fatal or nonfatal MI or CHD death) but were not powered statistically to determine their impact on total mortality.

The efficacy of statins to decrease incidence of important clinical outcomes (death, MI, revascularization, stroke, etc.) varies among primary prevention trials, likely the result of differences in baseline lipid abnormalities, patient populations, and LDL-C lowering of statin interventions.  Thus, the number needed to treat (NNT) to avoid a major coronary event ranges from 31 to 91; these are higher NNTs than found in secondary prevention (NNT to avoid a major coronary event was 12 in the 4S Trial) trials involving statins.

Secondary Prevention

There are an impressive number of clinical trials demonstrating a consistent benefit with statins for the secondary prevention of cardiovascular events.  The 4S, CARE, and LIPID studies were published prior to 1999 and consisted of patients with documented CHD.  In each of these studies, statin therapy significantly reduced the incidence of major coronary events, including CHD death and overall mortality in LIPID and 4S. The risk of stroke was also reduced in CARE and 4S.  Since 1999, there have been two additional secondary prevention trials evaluating the effect of statins on clinical endpoints and four evaluating statins after an acute coronary syndrome or percutaneous coronary intervention (MIRACL, LIPS, HPS, PROSPER, PROVE IT, and A to Z trials). These studies have convincingly shown that statins are beneficial for secondary prevention in patients with high as well as normal LDL-C, younger as well as older patients, and in stable coronary artery disease as well as acute coronary syndromes. Finally, numerous angiographic trials have demonstrated that statins slow the progression of atherosclerosis as measured by serial coronary angiography resulting in a trend towards reduced CHD events.

Thus, statins are the preferred pharmacotherapy for secondary prevention because of their effectiveness in reducing LDL-C, their safety and tolerability, and because of their demonstrated ability to reduce cardiovascular morbidity and mortality.

Moderate or high-dose statins have been associated with the best clinical results, regardless of baseline lipid levels, with LDL-C lowering in the range of 25-50 percent. Consequently, the emphasis on treatment of dyslipidemia for secondary prevention should focus on providing a statin to lower LDL-C at least 25 percent.

Table 7. Doses of Currently Available Statins Required to Attain an
Approximate 30% to 40% Reduction of LDL-C Levels (Standard Doses)*

Drug	Dose, mg/day	LDL Reduction, %
Atorvastatin	10†	39
Lovastatin	40†	31
Pravastatin	40†	34
Simvastatin	20–40†	35–41
Fluvastatin	40–80	25–35
Rosuvastatin	5–10‡	39–45
* Estimated LDL reductions were obtained from U.S. Food and Drug Administration (FDA) package inserts for each drug. † All of these are available at doses up to 80 mg. For every doubling of the dose above standard dose, an approximate 6% decrease in LDL-C level can be obtained. ‡ For rosuvastatin, doses available up to 40 mg; the efficacy for 5 mg is estimated by subtracting 6% from the FDA–reported efficacy at 10 mg. ( Jones et al., 1998)

Considerations-Statins

At this time, there is no convincing evidence that one statin is superior to another when administered in equally potent doses.  When statins are provided in doses that are approximately equivalent, a similar percent reduction in LDL-C and percentage of patients meeting their LDL-C goals can be achieved.  With regard to lowering TGs or elevating HDL-C, there does not appear to be major differences between agents.

Evidence exists for reducing CHD events with all of the currently available statins excluding rosuvastatin.  The choice of statin may depend upon degree of desired LDL-C lowering (see Appendix E for dose and expected LDL-C reduction).  Rosuvastatin should be reserved for those patients unable to achieve their LDL-C goals with maximally tolerate doses of other statins that possess clinical outcome and long-term safety data.

Titration and Follow-up

Prior to initiation of statin pharmacotherapy, the ACC/AHA/NHLBI Clinical Advisory Panel recommends determination of baseline liver function, with repeat testing at approximately 6-12 weeks and then annually or more frequently, if indicated (Pasternak et al., 2002).  This is based on manufacturer recommendations and the relative contraindication of these agents in patients with underlying liver disease.  Routine follow-up liver testing is not based on evidence but rather consensus. In the A to Z trial, significant elevations of liver enzymes were unusual (0.5 percent absolute increase in simvastatin 40/80 mg over placebo/simvastatin 20 mg) and most events occurred within the first 6 months of therapy (de Lemos et al., 2004). On the other hand, in PROVE-IT (2004), atorvastatin (80 mg) was associated with a statistically significant greater risk for elevation in liver enzymes compared to pravastatin (40 mg) (3.3 percent vs. 1.1 percent, P<0.001).

Muscle toxicity (myopathy and rhabdomyolysis) has been reported with all of the available statins.  The ACC/AHA/NHLBI clinical advisory panel identified certain factors that may predispose or place a patient at increase risk for developing muscle toxicity while receiving statins.  Some of those factors include, but are not limited to, advanced age (especially >age 80), female gender, frailty, renal insufficiency, polypharmacy, heavy alcohol use, and hypothyroidism. Baseline measurement of CK is not routinely recommended, however, it should be determined in patients who develop muscle soreness, tenderness, or pain.  All patients receiving statins should be educated regarding the recognition and reporting of any unexplained muscle pain, tenderness, or weakness.

The dose of statin should be adjusted at 6 to 12 week intervals until individual LDL-C goals are achieved, or statin doses have been maximized.

FIBRATES

Primary Prevention

Unlike the statins, relatively little evidence supports clinically relevant outcomes associated with the fibrates for primary prevention.  The best evidence for benefit is with gemfibrozil; it is not clear whether all fibrates possess a similar cardioprotective effect.

In the Helsinki Heart Study (HHS) (1987), there was a 34 percent relative risk reduction in cardiac outcomes (ARR 1.4percent, NNT=71), but no difference in death.  Clofibrate was studied in the World Health Organization (WHO) Cooperative Trial (1984).  Although there was a decrease in major CHD events, overall mortality was higher in the clofibrate group.  Fenofibrate is currently being studied in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial; results are expected in 2005.

The fibrates have relatively modest effect on LDL-C lowering; greater benefit is seen with triglyceride lowering, and increases in HDL-C.  Thus, until further evidence becomes available, the use of the fibrates in primary prevention should probably be limited to patients who are not good candidates for statin therapy, particularly for patients with high TGs or low HDL-C.

Secondary Prevention

Several studies have examined use of fibrates for secondary prevention.  One study (Coronary Drug Project, 1975) found no significant decrease in any clinical endpoints with use of clofibrate compared to placebo.  Two trials of bezafibrate (BIP and LEADER trials; bezafibrate is not available in U.S.) did not find benefit in primary outcomes (fatal and no-fatal CHD events), although in LEADER there was a benefit in non-fatal CHD events.  Likewise, a sub study of the Helsinki Heart Study (1993) also found no benefit of gemfibrozil in preventing clinical outcomes. However, the VA-HIT study of gemfibrozil found a significant decrease in combined MI and CV death in patients with low HDL (<40 mg/dL) and moderately elevated LDL-C (<140 mg/dL).  This trial is of significance to VA and DoD in that it was performed entirely within VA, and the relative risk reduction in hard clinical outcomes was similar to that of statin trials.  The newest fibrate, fenofibrate, has been studied in one small trial (DAIS) not statistically powered to detect clinical outcomes, although there was a decrease in atherosclerotic progression.  The FIELD study of fenofibrate therapy in diabetics should be available in 2005.  Although there is evidence to support a reduction in CHD events with gemfibrozil, it is not clear whether all fibrates possess a similar cardioprotective effect.

Considerations-Fibrates

As noted above, only VA-HIT has demonstrated a significant decrease in a primary endpoint of CHD events. Thus, given the preponderance of consistent benefit of statins, and equivocal results in all fibrate studies other than VA-HIT, statins are preferred therapy over fibrates for secondary prevention of CHD events.  However, patients with low HDL-C who are not candidates or intolerant for statins, should be given consideration for gemfibrozil.  Results of FIELD may offer additional evidence for benefit of fibrates in diabetic patients.

Fibrates are contraindicated in patients with severe liver or renal impairment including primary biliary cirrhosis. They are also contraindicated in patients with preexisting gallbladder disease, since all fibrates may increase cholesterol excretion into the bile increasing the risk for cholelithiasis.  If cholelithiasis is suspected, gallbladder studies should be performed and the fibrate discontinued if gallstones are found.

It is recommended that LFTs be measured prior to initiation of fibrate therapy and periodically during treatment, since clinically significant elevation of these tests has been reported. In addition, periodic monitoring of the complete blood count is recommended during the first 12 months of fibrate therapy since rare cases of serious hematologic abnormalities (leukopenia, thrombocytopenia, anemia, etc.) have been reported. In patients with serum creatinine values >2 mg/dL, administration of fibrates may worsen renal insufficiency, therefore, consideration of alternative therapy or of a lower dose is recommended. Myopathy and rhabdomyolysis have been reported with fibrate monotherapy, especially in those patients with impaired renal function. As a result, patients receiving monotherapy with fibrates should be educated regarding recognition and reporting of any unexplained muscle pain, tenderness, or weakness.

NIACIN

Primary Prevention

Niacin has the ability to reduce LDL-C and TGs and raise HDL-C, thus making it an attractive agent for primary prevention of CHD.  However, there are no clinical trials conducted in a primary prevention population to support a reduction in CHD events with niacin when used alone.

Secondary Prevention

Although niacin has been studied in several drug combination trials for secondary prevention, there is only one trial using niacin monotherapy. In the Coronary Drug Project (1975), patients receiving niacin had a significant decrease in nonfatal MI (Relative Risk Reduction [RRR] rate 27 percent, ARR 3.6 percent, NNT 28) and all stroke (RRR 24 percent, ARR 2.7 percent, NNT 37), but no benefit in overall mortality.

Niacin-Considerations

Niacin can be considered as second line treatment for the primary or secondary prevention of CHD in patients that are not candidates for or are intolerant of statins.  They also may be considered as add-on therapy for patients not meeting their lipid goals (LDL-C, HDL-C, and TG) with statins alone. (See combination treatment in Annotation Q2.)

Niacin is contraindicated in patients with significant liver impairment, active liver disease, unexplained transaminase elevations, active peptic ulcer disease, or arterial bleeding.

The primary limitation of niacin is the flushing side effects which can occur with any niacin products but can be minimized by giving low dose aspirin 30 minutes or a nonselective nonsteroidal anti-inflammatory drug (NSAID; e.g., ibuprofen) prior to niacin.  Higher doses of niacin may raise glucose or uric acid concentrations.  Two trials demonstrated the safety and efficacy of niacin in patients with diabetes. In the first study, an extended release niacin product (1500 mg/dL) was administered to diabetics managed by diet, oral hypoglycemics, or insulin (ADVENT, 2002). In the second study, up to 3 grams daily of crystalline niacin was administered to patients with diabetes and peripheral arterial disease (ADMIT, 2000). In either study, glycemic control was not clinically significantly changed in patients receiving niacin versus placebo.

Serious liver toxicity has been reported in patients receiving sustained release niacin in doses of >2 grams daily and less often in patients on crystalline niacin.  Providers choosing to switch crystalline niacin to extended release niacin or niaspan should begin at a low dose of the extended release product and titrate to the desired response.  Liver function should be measured prior to initiation of treatment, at 6-12 weeks and then periodically thereafter.  Niacin may cause rash and gastrointestinal (GI) symptoms.

BILE ACID SEQUESTRANTS OR RESINS

Primary Prevention

Bile acid sequestrants (BAS) have the ability to reduce LDL-C and slightly raise HDL-C; however, they may increase TG concentrations.  The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT, 1984) decreased CHD death and nonfatal MI (RRR 19 percent, ARR 1.6 percent, NNT 62), but there was no overall mortality benefit compared to placebo.

Secondary Prevention

There are no published trials evaluating the effect of resins (as monotherapy) on clinical endpoints in patients with CVD.  Resins have the ability to reduce LDL-C 10-27 percent, no effect on HDL-C, and either no effect or may increase triglyceride concentrations.  They may be considered as add-on therapy for those not achieving their LDL-C goals on niacin or moderate to maximum daily doses of statins (See combination therapy-Annotation Q2).

Considerations-BAS or Resin

The major limitations of resins are their poor tolerability (GI adverse effects), potential for drug interactions (if taken with other medications), and potential to further increase TGs in patients with elevated TG levels.

Resins may be considered as second-line therapy in patients unable to tolerate statins or other lipid-lowering treatments.  Resins may also be considered in combination with statins or other lipid-lowering drugs if LDL-C goals are not achieved with monotherapy (see combination therapy-Annotation Q2).

EZETIMIBE

Ezetimibe (ZetiaÒ) is the first in a new class of cholesterol lowering agents called the cholesterol absorption inhibitors.  It acts by selectively inhibiting absorption of cholesterol (dietary and biliary) at the brush border of the small intestine.

Aside from LDL-C lowering, there is no evidence to support a reduction in CHD events with ezetimibe when used alone for primary or secondary prevention of CHD.  However, it can be considered for lowering LDL-C in those patients either unable to tolerate and/or having an inadequate LDL-C lowering response to other lipid-lowering agents.

Considerations

When combined with statins, ezetimibe may increase the risk of elevated transaminases.  It should not be used with gemfibrozil, fenofibrate, or enofibrate micronized.

 

FISH OIL SUPPLEMENTS (N-3 Polyunsaturated Fatty Acids or N-3 PUFA or Omega-3 Fatty Acids)

In NCEP ATP-III, the use of fish oil supplementation or -3 PUFAs is discussed briefly.  As part of the report, n-3 PUFAs (e.g., fish, fish oils, or high linolenic acid oils) in lower doses (1-2 g/day) are mentioned for the prevention of CHD.  ATP-III concluded that the strength of the available clinical trial evidence for this use was moderate and states that more definitive clinical trials are needed prior to routinely recommending n-3 PUFAs for primary or secondary prevention of CHD (NCEP ATP-III, 2002; DART-Burr et al., 1989; Singh et al., 1997; GISSI, 1999).

Based upon the evidence from two systematic reviews (Harris, 1997; Farmer et al., 2001) and several other randomized controlled trials (Harris, 1997; Nordoy et al., 2001; Durrington et al., 2001; Stalenhoef et al., 2000), n-3 PUFAs, in doses of 3-4 grams per daily are safe and efficacious in lowering TGs and are an alternative to fibric acids (gemfibrozil or fenofibrate) or nicotinic acid for the treatment of hypertriglyceridemia.