Functional Evaluation of Lipid-Lowering Therapy by Pravastatin
To the Editor:
With great interest we read the article of Dr Aengevaeren and coworkers on further functional aspects of lipid-lowering therapy in patients with coronary artery disease as derived from the REGRESS Study.1 In comparison to placebo, 2 years of treatment with 40 mg of pravastatin resulting in a decrease of LDL-cholesterol by 23% not only preserved coronary flow reserve (videodensitometric hyperemic mean transit time of contrast media after intracoronary injection of papaverine) but also proved to be superior in respect to its influence on clinical symptoms. Anginal functional class according to the criteria of the Canadian Cardiovascular Society2 demonstrated a change of 2.1±0.5 to 1.8±0.8 in the verum versus 1.4±1.0 to 1.7±1.0 in the placebo group, resulting in a mean difference of 0.7 between groups (P=.03). Even though the absolute difference in patients treated was not reported to be significant this is the first placebo-controlled trial in patients with stable coronary artery disease, which describes not solely antiischemic properties of LDL-cholesterol reduction as other clinical studies have done previously3 4 5 but also supplies evidence for relative antianginal properties when compared to the natural course of the disease over a period of 2 years. As morphologic regression of coronary arteriosclerosis was minimal functional, LDL-cholesterol dependent determinants of coronary blood flow like a decreased coronary vasomotor tone in the epicardial conductance6 7 and microvascular resistance vessels5 are likely to account for the therapeutic effect.
Another substudy of the REGRESS-Study by Dr Boven and coworkers reported antiischemic effectiveness of the same therapeutic regimen in patients who underwent 48-hour ambulatory ST-Holter monitoring before and after 2 years of treatment.4 Unfortunately, even though both studies are presumably derived from the same study protocol, Dr Boven and coworkers did not report the effect of treatment on the functional clinical impairment due to angina pectoris. A variability of the ischemic threshold at the level of the epicardial conductance vessels documented by an increased time to ischemic end points during standardized exercise tests after the intake of fast-release nitrates can be found in at least 30% of the patients with stable coronary artery disease.8 It would be interesting to know, whether Dr Boven and coworkers observed a particular benefit of treatment in patients with a variable threshold for the onset of ST-segment depression and anginal symptoms for example defined by a variability in heart rate of >20 bpm at the onset of pathologic changes during the 48 hours ST-Holter recordings.9 In case this was true, it would probably prove that lowering of LDL-cholesterol has an absolute and significant antianginal effect when compared with placebo in this subset of patients with a variable threshold of ischemic changes.
Regardless of its beneficial effect in the secondary prevention of coronary artery disease antianginal properties of LDL-cholesterol reduction would have important implications in particular for the treatment of patients with end-stage coronary artery disease and chronic refractory angina pectoris as they are currently subject to studies on various new anti-ischemic interventions such as low-dose intermittent urokinase therapy, spinal cord stimulation, and transmyocardial laser revascularization (see also Reference 10). These patients without a feasible option for successful coronary revascularization are characterized by anginal functional class III or IV resulting in a high rate of anginal episodes (23.4±11.4 episodes/wk) despite maximally tolerated antianginal combination therapy (nitrates, β-blockers, calcium antagonists).10 If antianginal effectiveness of LDL-cholesterol reduction can be shown based on the considerations mentioned above and if they occurred within a short period as implied by the antiischemic effectiveness after only 3 months of treatment in the study by Dr Gould and coworkers,5 this would call for intensified lipid-lowering treatment with documented LDL-cholesterol levels ranging ≈100 mg/dL as a necessary precondition before alternative treatment modalities are used.
- Copyright © 1998 by American Heart Association
Aengevaeren WRM, Uijen GJH, Jukema JW, Bruschke AVG, van der Werf T. Functional evaluation of lipid-lowering therapy by pravastatin in the Regression Growth Evaluation Statin Study (Regress). Circulation. 1997;96:429–435.
Andrews TC, Raby K, Barry J, Naimi CL, Allred E, Ganz P, Selwyn AP. Effect of cholesterol-lowering on myocardial ischemia in patients with coronary artery disease. Circulation. 1997;95:324–328.
van Boven ADJ, Jukema JW, Zwinderman AH, Crijns HJGM, Lie KL, Bruschke AVG, on behalf of the Regress Study Group. Reduction of transient myocardial ischemia in addition to the conventional treatment in patients with angina pectoris. Circulation. 1997;94:1503–1505.
Gould KL, Martucci JP, Goldberg DI, Hess MJ, Edens RP, Latifi R, Dudrick SJ. Short-term cholesterol lowering decreases size and severity of perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronary artery disease: a potential noninvasive marker of healing coronary endothelium. Circulation. 1994;89:1530–1538.
Egashira K, Hirooka Y, Kai H, Sugimachi M, Suzuki S, Inou T, Takeshita A. Reduction in serum cholesterol with pravastatin improves endothelium dependent coronary vasomotion in patients with hypercholesterolemia. Circulation. 1994;89:2519–2524.
Maseri A. Medical therapy of chronic stable angina pectoris. Circulation. 1990;82:2258–2262.
The antianginal properties of lipid-lowering therapy by HMG-CoA inhibitors are a potential challenging feature. The basic mechanism of the antianginal effect is not yet completely understood. Although improved endothelial function of epicardial conductance and/or resistance vessels probably is the major contributor to this antianginal effect, antiplatelet activity and decreased blood viscosity might also be properties of additional benefit.R1 R2 R3
“Whether patients with variable threshold angina pectoris might have an increased benefit over patients with stable angina” is an interesting question, for which we have analyzed the data again. In the ambulatory ECG substudy of REGRESS a reduction of 1.23 episode was found in the pravastatin group versus a reduction of 0.53 episode in the placebo group (P=.047).R4 Patients with ischemia on ambulatory ECG decreased from 28% to 19% in the pravastatin group versus an increase from 20% to 23% in the placebo group (P=.021). Total duration of ischemic burden was also significantly reduced by pravastatin as compared with placebo. When we now divide the periods of ischemia in groups with a variability in heart rate of more or less than 20 bpm during ischemia, we found that in the group with a change ≥20 bpm, patients receiving pravastatin showed an increase from 1.11 to 1.83 episode per patient (P=.001) and patients receiving placebo an increase from 1.27 to 1.96 (P=.14), respectively. In patients with ischemic episodes and a difference of <20 bpm, patients receiving pravastatin showed a reduction from 4.15 to 3.18 ischemic episode per patient (P=.27), whereas patients receiving placebo showed an increase from 3.06 to 3.64 episode per patient (P=.077). These findings suggest that pravastatin therapy is more effective in ischemic episodes with a low rise in heart rate. These findings support the hypothesis that lipid lowering by HMG-CoA inhibitors has an anti-ischemic effect through an improvement of endothelial function of the coronary (micro) circulation. Most of the episodes of transient ischemia in this study were asymptomatic. The change in angina pectoris classification for this group of patients was not available.
We agree with Dr Schoebel and colleagues that lipid lowering by HMG-CoA inhibitors should be an early step in the treatment of patients with angina pectoris, independent from the cholesterol level to prevent further progression of coronary artery disease. The positive effect on anginal complaints might be advantageous, but at this moment the degree of functional improvement from HMG-CoA inhibitors is largely unknown. Therefore, to state that HMG-CoA inhibitors are a necessary precondition in patients with chronic refractory angina pectoris because of the antianginal properties is questionable. The degree of improvement in myocardial perfusion in absolute terms in the pravastatin group of REGRESS was very limited, It was the placebo group that deteriorated over 2 years of therapy.R5 These results are in agreement with the LAARS study; in this study patients with extensive coronary artery disease were randomized between LDL-apheresis+simvastatin 40 mg once daily versus simvastatin 40 once daily only. After 2 years of treatment, myocardial perfusion and exercise-induced ischemia improved significantly in the group of patients with LDL-apheresis+simvastatin, whereas patients on simvastatin had no change in myocardial perfusion or exercise-induced ischemia.R6 R7 In this context it is doubtful if HMG-inhibitors in patients with end-stage coronary artery disease and chronic refractory angina pectoris will have a dramatic effect on anginal complaints.
Whether lipid lowering with LDL-cholesterol levels ≈100 mg/dL (2.6 mmol/L) are necessary for functional improvement neither is evident. There are indications that the positive effect of lipid-lowering therapy is not attributed to the degree of lipid lowering but rather to the use of HMG-CoA inhibitors. In the 4S and CARE trial there was no close relation between the degree of lipid lowering and the decrease in major cardiac events.R8 R9 Furthermore, drugs of a total different class may improve endothelial function without lipid lowering.R10
Egashira K, Hirooka Y, Kai H, Sugimachi M, Suzuki S, Inou T, Takeshita A. Reduction of serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation. 1994;89:2519–2524.
Lacoste L, Lam JY, Letchacovski G, Solymoss CB, Waters D. Hyperlipidemia and coronary disease: correction of the increased thrombogenic potential with cholesterol reduction. Circulation. 1995;92:3172–3177.
van Boven AJ, Jukema JW, Zwinderman AH, Crijns HJGM, Lie KL, Bruschke AVG, on behalf of the Regress Study Group. Reduction of transient myocardial ischemia with pravastatin addition to the conventional treatment in patients with angina pectoris. Circulation. 1996;94:1503–1505.
Aengevaeren WRM, Uijen GJH, Jukema JW, Bruschke AVG, van der Werf T. Functional evaluation of lipid-lowering therapy by pravastatin in the Regression Growth Evaluation Statin Study (REGRESS). Circulation. 1997;96:429–435.
Kroon AA, Aengevaeren WRM, van der Werf T, Uijen GJH, Reiber JHC, Bruschke AVG, Stalenhoef AFH. The LDL-Apheresis Atherosclerosis Regression Study (LAARS): effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis. Circulation. 1996;93:1826–1835.
Aengevaeren WRM, Kroon AA, Stalenhoef AFH, Uijen GJH, van der Werf T. Low density lipoprotein-apheresis improves regional myocardial perfusion in patients with hypercholesterolemia and extensive coronary artery disease: the LDL-Apheresis Atherosclerosis Regression Study (LAARS). J Am Coll Cardiol. 1996;28:1696–1704.
The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:383–389.
Sacks FM, Pheffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun CC, Davies BR, Braunwald E, for the Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001–1009.
Mancini GBJ, Henry GC, Macaya C, O’Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra H, Luscher TF, Klibaner MI, Haber HE, Uprichard AC, Pepine CJ, Pitt B. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease: the TREND Study. Circulation. 1996;94:258–263.