Intravascular Ultrasound Determinants of Future Coronary Stent Thrombosis

READERS’ COMMENTS Challenges of Meta-Analyses Pooling Non-Randomized Controlled Studies We read with interest the recent meta-analysis by Merla et al1 pooling data from 2 randomized trials and 7 cohort studies on the risk-benefit balance of statin pretreatment for percutaneous coronary intervention. However, we must caution that the investigators’ conclusions are undermined by several analytic drawbacks. Indeed, Merla et al1 pooled unadjusted raw event rates into odds ratios as provided from nonrandomized trials, dismissing adjusted risk estimates. Unfortunately, this approach may lead to biased conclusions, because no adjustment is performed and taken into account during meta-analytic pooling with respect to the potential presence of selection bias in these nonexperimental studies.2 We suggest that the investigators take full advantage of the Review Manager freeware they already used (RevMan version 4.2; The Cochrane Collaboration, Copenhagen, Denmark), by pooling multivariate adjusted odds ratios from individual studies using generic inverse variance weighting.3 Moreover, Merla et al1 inappropriately appraised the internal validity of primary studies using a quantitative scale of quality (from Downs and Black4), yet this pseudoquantitative method is fraught with major problems and may provide biased results. We recommend a more comprehensive and descriptive quality appraisal, as also advocated by the Cochrane Collaboration and other authorities.5,6 In conclusion, despite their clinical relevance, the data reported by Merla et al1 as they stand should be mostly considered as hypothesis generating. Conversely, by addressing our comments, their impact on readers should be substantially strengthened.

*Letters (from the United States) concerning a particular article in The American Journal of Cardiology威 must be received within 2 months of the article’s publication, and should be limited (with rare exceptions) to 2 double-spaced typewritten pages. Two copies must be submitted.

Marzia Lotrionte, MD Rome, Italy Giuseppe G. L. Biondi-Zoccai, MD Imad Sheiban, MD Turin, Italy 28 August 2007

1. Merla R, Reddy NK, Wang F, Uretsky BF, Barbagelata A, Birnbaum Y. Meta-analysis of published reports on the effect of statin treatment before percutaneous coronary intervention on periprocedural myonecrosis. Am J Cardiol 2007;100:770 –776. 2. Altman D. Systematic reviews of evaluations of prognostic variables. In: Egger M, Davey Smith G, Altman D, eds. Systematic Reviews in Health Care: Meta-Analysis in Context. London, United Kingdom: BMJ, 2001:228 – 247. 3. Biondi-Zoccai GG, Lotrionte M, Agostoni P, Abbate A, Fusaro M, Burzotta F, Testa L, Sheiban I, Sangiorgi G. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart J 2006;27:2667–2674. 4. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Commun Health 1998; 52:377–384. 5. Juni P, Witschi A, Bloch R, Egger M. The hazards of scoring the quality of clinical trials for meta-analysis. JAMA 1999;282:1054 –1060. 6. The Cochrane Collaboration. The Cochrane Handbook for Systematic Reviews of Interventions. Available at: http://www.cochrane.org/resources/handbook/. Accessed August 27, 2007. doi:10.1016/j.amjcard.2007.09.002

Cardiac Function Before and After Surgery for Pectus Excavatum In our review of 1600 reports from PubMed of pectus excavatum, cardiac function pre- and post-operative was recorded from 5 studies. We failed to include the 1998 publication work of Kowalewski and colleagues1 because we found that the 1999 paper was based on indirect measures and we believed it was reporting the same population as in the 1998 one. By our study requirements, “when a center published more than once on a series of cases , we included only the later publication.” Unfortunately, we failed to appreciate the fact that the study published in 1998 included direct measurements of left ventricular diameter and stroke volume2 in 34 operated patients and they re-

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ported an improvement of 15% in function. Our Table 1 included only 4 studies with 76 patients with generally acceptable methods, all of which had no change or a small decrease in cardiac dimensions or stroke volume. (One study of left ventricular diameter not acceptable was based on M-mode determinations of left ventricular diameter raised by an exponential; even their controls had large increases!) If Kowalewski’s 34 patients1 are added to our previous 76, the total number of patients with acceptable methods is 110, and 34 (31%) had an improvement in left ventricular function. We should point out the difficulty in assessing patients’ ventricular dimensions accurately due to the funnelshaped chest, whereas after operation the standard echocardiographic windows are often restored. We believe that our conclusion stands, “the published data fail to show convincing improvement in either pulmonary or cardiac function after thoracic surgery for pectus excavatum.” (The pulmonary function clearly is worse3.) Warren G. Guntheroth, MD Philip S. Spiers, MD

1. Kowalewski J, Barcikowski S, Brocki T. Cardiorespiratory function before and after operation for pectus excavatum: medium-term results. Eur J Cardiothorac Surg1998;13:275– 279. 2. Kowalewski J, Brocki T, Dryjanski T, Zolynski K, Kotyysz R. Pectus excavatum: increase of right ventricular systolic, diastolic, and stroke volume after surgical repair. J Thorac Cardiovasc Surg 1999;118:92–93. 3. Malek MH, Berger DE, Marelich WD, Coburn JW, Beck TW, Housh TJ. Pulmonary function following surgical repair of pectus excavatum: a meta-analysis. Eur J Cardiothorac Surg 2006;30:637– 643. doi:10.1016/j.amjcard.2007.09.003

Intravascular Ultrasound Determinants of Future Coronary Stent Thrombosis We read with interest the report by Okabe et al,1 who endeavored to identify intravascular ultrasound parameters during the implantation of drug-eluting stents that predict stent thrombosis. We www.AJConline.org

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wish to point out a few factors that limit the interpretation of this study. First, by the investigators’ acknowledgment, the study was small, retrospective, and not matched for important baseline characteristics such as gender, age, and, importantly, in-stent restenosis. There was also a significant difference between groups in glycoprotein IIb/IIIa receptor blocker use, but no reporting of clinical presentation before the index procedure, which could have influenced outcomes. Finally, there is no mention as to whether the analysis of data or intravascular ultrasound images had been performed by the investigators in a blinded manner or not. If key aspects of the study, such as group selection and image analysis, were performed in a nonblinded manner, this would further weaken the study, given the modest absolute differences detected between the groups. Although the study provides an interesting discussion of intravascular ultrasound and stent thrombosis, it does not provide any new insights into this phenomenon with respect to drug-eluting stents, and perhaps a comparison with a bare-metal stent cohort in a more statistically robust manner may be more enlightening. Ravinay Bhindi, MBBS, PhD Luca Testa, MD William van Gaal, MBBS Oxford, United Kingdom 1 September 2007

1. Okabe T, Mintz GS, Buch AN, Roy P, Hong YJ, Smith KA, Torguson R, Gevorkian N, Xue Z, Satler LF, et al. Intravascular ultrasound parameters associated with stent thrombosis after drug-eluting stent deployment. Am J Cardiol 2007;100:615– 620. doi:10.1016/j.amjcard.2007.09.073

Effect of Cocaine on Cardiac Biomarkers Afonso et al1 nicely reviewed the deleterious cardiovascular effects of cocaine use in their report titled “Crack Whips the Heart: A Review of the Cardiovascular Toxicity of Cocaine.” They discussed cocaine-induced chest pain and stated that “although chest pain is the most common presenting symptom, the incidence of enzymatic or biomarker evidence of acute myocardial infarction (MI) or myonecrosis is relatively low.” Ruling out MI is indeed of utmost importance in the acute setting

of cocaine-induced chest pain. Therefore, further elaboration on the interpretation of cardiac biomarkers in this setting is warranted. The specificity of cardiac biomarkers can be altered by recent cocaine use, making them difficult to interpret in cocaine-associated MI. Specifically, the serum creatinine kinase level is not reliable, nor is the MB fraction in cocaine-associated MI, possibly because of cocaine-induced hyperthermia, increased skeletal muscle activity, and rhabdomyolysis.2–5 Up to half of cocaine users can have increased serum creatinine kinase levels irrespective of concurrent MI.6 Mean myoglobin levels can also be higher in cocaine users without MIs.5 To the contrary, studies have shown that troponin I levels are more reliable for detecting cocaine-associated MI and are associated with worse long-term outcomes.2–5 Knowledge of the effect of cocaine on cardiac biomarkers may avert unnecessary diagnostic intervention to rule out coronary artery disease. John R. Kapoor, MD, PhD Stanford, California 28 September 2007

1. Afonso L, Mohammad T, Thatai D. Crack whips the heart: a review of the cardiovascular toxicity of cocaine. Am J Cardiol 2007;100: 1040 –1043. 2. Tokarski GF, Paganussi P, Urbanski R. An evaluation of cocaine-induced chest pain. Ann Emerg Med 1990;19:1088 –1092. 3. Kontos MC, Anderson FP, Ornato JP. Utility of troponin I in patients with cocaine-associated chest pain. Acad Emerg Med 2002;9: 1007–1013. 4. McLaurin M, Apple FS, Henry TD. Cardiac troponin I and T concentrations in patients with cocaine-associated chest pain. Ann Clin Biochem 1996;33:183–186. 5. Hollander JE, Levitt MA, Young GP. Effect of recent cocaine use on the specificity of cardiac markers for diagnosis of acute myocardial infarction. Am Heart J 1998;135:245–252. 6. Hollander JE, Hoffman RS, Gennis P, Fairweather P, DiSano MJ, Schumb DA, Feldman JA, Fish SS, Dyer S, Wax P. Prospective multicenter evaluation of cocaine associated chest pain. Acad Emerg Med 1994;1:330 –339.

in patients with chronic heart failure (HF). The recent review by Böhm1 discusses the current evidence comparing ACE inhibitors with ARBs and their combination on various outcomes data. Several studies are cited demonstrating the beneficial effects of ACE inhibitors in patients with chronic HF, and it is noted that that these benefits are shared by ARBs, which are also useful in patients intolerant to ACE inhibitors. However, there is no mention of the published data providing evidence for the potential benefits of the combination of ACE inhibitors and ARBs in patients with chronic HF. The Valsartan Heart Failure Trial (Val-HeFT) evaluated 5,010 patients with left ventricular systolic dysfunction, left ventricular dilatation, and New York Heart Association functional class II to IV symptoms.2 It was found that although the addition of valsartan to optimal ACE inhibitor therapy (in 93% of patients) led to no significant benefit in all-cause mortality, the combined end point of mortality and morbidity, including episodes of cardiac arrest, HF hospitalizations, or the use of intravenous inotropes or vasodilators was significantly reduced in the valsartan group. The primary outcome of cardiovascular death or HF hospital admissions was also significantly reduced in patients receiving candesartan on top of background ACE inhibitor therapy in 1,276 patients with HF in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)–Added trial.3 Finally, a recent meta-analysis, taking into account data from the Val-HeFT and CHARM-Added trials, showed that although combination therapy with ACE inhibitors and ARBs did not change all-cause mortality, it did lead to significant reductions in HF hospitalizations.4 Thus, combination therapy with ARBs on top of an HF regimen that includes ACE inhibitors may provide significant morbidity benefit for symptomatic patients.

doi:10.1016/j.amjcard.2007.10.003

Effect of Combination AngiotensinConverting Enzyme and Angiotensin Receptor Blocker Therapy on Heart Failure Mortality and Morbidity Studies now demonstrate the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)

John R. Kapoor, MD, PhD Stanford, California 12 October 2007

1. Böhm M. Angiotensin receptor blockers versus angiotensin-converting enzyme inhibitors: where do we stand now? Am J Cardiol 2007; 100:38J– 44J. 2. Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic