N. Determine Risk for CVD and Establish the Goal for Interventions

objective

Startify patient according to risk for CV event.

background

Once a 10-year risk has been calculated, the goals of therapy can be determined based upon the absolute 10-year risk.  Risk calculation is not necessary for patients with documented CVD or CVD equivalent, and secondary prevention for these patients is appropriate.

recommendations

1. Goals of lipid lowering therapy should be tailored to risk level and based upon the balance between benefits, risks, and patient preferences.  [C]

Goals of Therapy for Secondary Prevention

2. LDL-C should be lowered to <100 mg/dL for patients with a recent ACS.  [A]
3. An optional lower target for LDL-C (<70 mg/dL) may be considered for very high-risk post-ACS patients.  [B]
4. LDL-C should be lowered to <100 mg/dL for patients with previous documented CHD or CVD equivalent (DM with other major risk factors) for secondary prevention.  [A]
5. LDL-C should be lowered to <130 mg/dL for patients with DM without other major risk factors for secondary prevention.  [C]

Goals of Therapy for Primary Prevention

6. LDL-C should be lowered to <100 mg/dL for patients with high 10-year risk >20 percent.  [B]
7. LDL-C should be lowered to <130 mg/dL for patients with intermediate 10-year risk (15-20 percent).  [B]
8. LDL-C should be lowered to <130 mg/dL for patients with intermediate 10-year risk (10-14 percent). [C]
9. LDL-C should be lowered to <160 mg/dL for patients with low 10-year risk.  [I]
10. LDL-C reduction of 30-40 percent from baseline may be considered an alternative therapeutic strategy for patients who can not meet the above goal.

Table 2. Goals of Lipid Lowering Therapy

	Risk Category	Number of Risk Factors (RF)	10-Year Risk	LDL-C Goal mg/dL *	Remarks
1	Recent ACS	N/A	N/A	<100	Option <70 mg/dL
2	CHD or equivalent (DM with other risk factors)	N/A	N/A	<100	Optional <130 for DM with no other risk factors
3	High	2 + RF	≥ 20%	<100	--
4	Intermediate	2 +RF	15 - 20%	<130	--
5			10 - 14% **	<130	--
6	Low	0-1 RF	N/A	<160	--

N/A = Not applicable
*    Recommendations are based on quality of evidence for improving CVD outcomes.
** There is insufficient evidence at this time to recommend routine screening for other risk markers not included in the risk index (e.g., FH, hsCRP, metabolic syndrome, depression), or evidence of significant atherosclerotic burden (e.g., high coronary artery calcification scores, intima medial thickness, abnormal brachial reactivity, or abnormal ankle-brachial index).  These risk markers have independent prognostic value whereby abnormal values can shift risk percent upward across treatment thresholds with more robust evidence for efficacy.  Therefore, they may be useful in the intermediate risk patient for whom it is less convincing that drug therapy would have a meaningful impact on outcomes.  Example: Patient with a 10-year risk of 13 percent in whom an abnormal test with a proven adjusted relative risk of >2 would shift the patient to a high-risk category (across a 20 percent, 10-year risk threshold).

discussion

Targeting therapy to risk is based on the findings from multiple intervention trials that the magnitude of benefit is closely related to the short-term predicted risk of a CHD event (Wilson et al., 1998; Grundy, 2004).  Other than the Post-Coronary Artery Bypass (CABG) trial (1997) and the recent (TNT) trial (2005), there are no published clinical outcomes trials that have used LDL goals as a pre-specified target of therapy.  Thus, determining LDL goals for therapy is based on limited objective data.

Prospective epidemiologic evidence indicates that the incidence of CHD is proportional to serum TC and LDL-C.  Thus, it is theoretically rational that the lowering of CVD risk will be directly related to the lowering of cholesterol.  Whether this relationship continues to be linear at very low LDL levels (<100 mg/dL) is a subject of continuing research.

Secondary Prevention

In ACS, there are several trials among patients who derived improved outcomes from aggressive LDL lowering to mean LDL levels well below 100 mg/dL (PROVE-IT, 2004; MIRACL, 2001; REVERSAL, 2004).  In PROVE-IT, ACS patients randomized to high dose atorvastatin with an LDL goal of less than 70 mg/dL achieved fewer major cardiovascular events compared to patients treated to a goal of less than 100 mg/dL on pravastatin.  There appeared to be a threshold effect where benefits were most pronounced among patients with a baseline LDL 125 mg/dL or greater (Absolute Risk Reduction [ARR] 8.5 percent) than those with baseline LDL of less than 125 mg/dL (ARR 2.1 percent).  Thus, most benefit will occur in patients with higher starting LDL levels who achieve at least a goal of <100 mg/dL.  Given the overall nature of the PROVE-IT trial to achieve a goal of <70 mg/dL, it may be reasonable to pursue an optional therapeutic goal of LDL-C <70 mg/dL in patients with ACS (Grundy et al., 2004).

Numerous secondary prevention high quality randomized trials using statin medications have shown reduction in CHD morbidity and mortality.  The mean “on-treatment” LDL-C of the cohorts in these trials was well below <120 mg/dL (HPS, 2002; PROVE-IT, 2004; A to Z, 2004; TNT, 2005; CARE, 1996).  While several of these trials had mean on-treatment LDL levels <100 mg/dL, and NCEP recommends a goal of <100 mg/dL in such patients, such a threshold has not been sufficiently proven in stable CHD patients or primary prevention high-risk cohorts.  However, more recently there have been two trials that showed benefit to more aggressive treatment in stable high-risk secondary prevention patients.  LDL-C was lowered in HPS from 130 to 89 mg/dL and in TNT from 99 to 78 mg/dL.  Both trials showed significant improvements in multiple cardiovascular outcomes.  In HPS, there was no threshold effect for starting therapy, with equal relative risk benefit among the tertiles of baseline LDL.  More research is needed to confirm the efficacy and safety of aggressive LDL-lowering therapy to levels below 100 mg/dL in stable CHD patients.

Primary Prevention

 Among patients without a history of CVD but who have high predicted risk (typically men over age 50 and women over age 60 who have multiple other risk factors), which is comparable to those with a history of clinical CHD, it is rational to treat such patients as aggressively as one would for those with CHD (i.e., goal <100 mg/dL) (NCEP III, 2002; ASCOTS-LLA, 2003 [which had patients with HTN with three other risk factors]; Haffner et al., 1998).

Several primary prevention statin trials (which included only patients with LDL-C >130 mg/dL) demonstrated significant CHD risk reduction among intermediate- and high-risk patients without a history of CVD.  All these trials had baseline LDL levels greater than 130 mg/dL, and achieved on-treatment LDL levels in the low 100s mg/dL.  The AFCAPS/TexCAPS trial (1998) achieved a mean LDL-C of <120 mg/dL, the WOSCOPS study (1995) ~140 mg/dL, and the ASCOT-LLA ~130 mg/dL (2003).  Sub-group analyses of the primary prevention trials indicates that a vast majority of the improved outcome occurred in patients whose 10-year risk exceeded 20 percent, and correlated with reduction in LDL.  There was less improvement (but statistically significant) in those with 10-year risk in the 15-20 percent category, and there was no statistically significant risk reduction among those with 10-year risk <15 percent.

Although the short-term risk may be low in those with a 10-year FRS <10 percent, the long-term relative risk associated with high LDL-C (>160 mg/dL) is high enough that lipid lowering interventions to lower the LDL-C to <160 mg/dL would be reasonable to modify long-term risk.

Goals: Specific LDL Absolute Values Versus Percent LDL Reduction

Some experts argue that it is the percentage drop in LDL, not the absolute LDL achieved that is important in achieving benefit.  In HPS, there was similar risk reduction in those who received a standard dose of simvastatin, regardless of final LDL.  Specifically, reduction of CHD events was similar for those with final LDL of 116, 116-135, and those greater than 135 mg/dL.  This strategy recognizes that significant clinical benefit occurs with 30-40 percent LDL reduction regardless of final LDL, and attempting to drive LDL down further with higher doses of statins or combination therapy may expose patients to additional adverse events without proven efficacy.  The SEARCH and the IDEAL trials currently underway may give additional insight into whether aggressive treatment with statins will address the value of LDL absolute values or percent reduction as the more valid strategy.

Why Does the VA/DoD Guideline Differ from NCEP in their LDL Goals?

Most NCEP recommendations are consensus statements designed to guide the broad clinical field of dyslipidemia.  Many of the recommendations are based on observational studies with rational inferences based on biologic plausibility.  Clinical practice guidelines have to guide practical decision-making in real world practice among patients for whom there are most often no applicable clinical trials, and in whom there is an intricate balance of patient preferences, co-morbidities, medication interactions, and other psychosocial factors.  Therefore, the VA/DoD Dyslipidemia Guidelines Working Group was tasked to design a rigorous evidence-based guideline whereby recommendations were based on high quality clinical data (typically randomized controlled trials [RCT] using hard outcomes).  The Guideline Working Group’s knowledge of the DoD and VHA clinical practice settings allows for adaptation of these recommendations to our specific system of care.  This is the basis upon which there are differences between NCEP and the VA/DoD CPG recommendations.  The decisions on treatment will always be guided by clinical judgment of the providers who may strive to achieve lower LDL-C goals for their individual patient.

Most high-risk patients (those with CVD or CVD equivalent) will benefit from statin therapy, regardless of baseline LDL.  However, patients with very high baseline LDLs may have difficulty in achieving LDL of less than 100 despite moderate to high dose statin therapy (greater than 25 percent reduction in LDL-C).  Most recent studies achieving very low treatment LDLs started with low baseline LDL (mean LDL-C in HPS was 131 mg/dL; median LDL-C in PROVE-IT was 106 mg/dL) opposed to 188 mg/dL in 4S.  Thus, in those patients with a high LDL baseline, the full risk-benefit of combination drug therapy or even high dose statin therapy is unknown, especially among patients with significant disease comorbidities or concomitant drug therapy.  The data from meta-analyses of the major statin RCTs indicate that an LDL-C reduction of 30-40 percent from baseline may be considered a therapeutic strategy for patients who can not meet the above goal.