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EDITORIAL COMMENT

A Long-Term Perspective onShort-Term Outcomes*

Mark A. Hlatky, MD

O utcomes matter in cardiology. We needreliable data about long-term outcomes toevaluate which treatments work, whether

they do more good than harm, and which patientsbenefit the most. The outcomes that matter most arethe ones that patients and their families care about:death and major complications such as myocardialinfarction (MI) and stroke. (Other patient-centeredoutcomes, such as symptoms, functional capacity,and quality of life, are also important, even thoughthey are more difficult to ascertain reliably.) Thetremendous progress we have made in treating car-diovascular disease is the direct result of clinicalresearch studies that have evaluated treatmentsrigorously and followed up patients to documenttheir clinical outcomes.

Even though there is consensus that documentingoutcomes is important, there is great variation amongclinical research studies in the length of follow-up.Long-term follow-up seems like a good idea, buthow long? Some conditions may have a clear naturaltime scale during which all the key outcomes shoulddevelop and the full effects of treatment ought tobecome evident. Acute illnesses have a shorter nat-ural time scale than chronic diseases, but an acuteillness may have long-lasting effects. An acute MIdevelops suddenly, with a narrow time window ofa few hours during which coronary reperfusion iseffective and a subsequent healing period of a fewweeks, but it leaves permanent damage that mayhave long-term sequelae (e.g., susceptibility to late

*Editorials published in the Journal of the American College of Cardiology

reflect the views of the authors and do not necessarily represent the

views of JACC or the American College of Cardiology.

From the Stanford University School of Medicine, Stanford, California.

Dr. Hlatky has reported that he has no relationships relevant to the

contents of this paper to disclose.

arrhythmia or heart failure). Also, the underlyingcoronary atherosclerosis remains and provides thesubstrate for a future cycle of acute occlusion andrecurrent MI. So what is the “natural time scale” forassessing outcomes of an acute MI? Large-scale clin-ical trials generally measure primary outcomes at 4 to6 weeks, which is long enough to identify short-termtreatment effects yet short enough to be reasonablypractical: a short-term time frame to assess an acutedisease treated with a 1-time therapy.

But is a few weeks long enough to assess the resultsof therapy for acute MI? Timely reperfusion mightprovide long-term benefits by limiting myocardialdamage, but implantation of a coronary stent mayhave long-term consequences, such as stent throm-bosis. We can’t document late effects of treatment,either good or bad, unless we follow up patients overthe long term. Unfortunately, we usually do not.

Why is long-term follow-up important? Manytreatments have effects that will not be immediatelyevident, so short-term follow-up would not capturethe full lifecycle of these therapies. For instance,implanted devices may fail after a few years, anddrug therapy might take time to alter the naturalhistory of disease; the survival curves for niacin andplacebo in the Coronary Drug Project began to sepa-rate only after 8 years of follow-up (1). In contrast,10-year follow-up studies of patients treated withthrombolysis for acute MI showed parallel survivalcurves after 1 year, with no evidence of either latebenefit or late harm from treatment (2,3).

There are many barriers to obtaining long-termfollow-up. Research sponsors want results quickly;commercial sponsors want to have their productsapproved without delay; and even the National In-stitutes of Health wants its investments in research tohave tangible results soon. Consequently, length offollow-up may be a few weeks at most, and 1 yearof follow-up is often considered “long-term.” It is

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expensive to follow up patients long-term, especiallyif research staff must locate and contact each indi-vidual over many years. It would be much simplerand much less expensive to document outcomesusing routinely collected data, such as hospitaldischarge and vital statistics records. My colleaguesand I recently showed that linking clinical trial datawith Medicare claims could provide a reliable methodto identify late cardiac events (4), which suggests thatlong-term surveillance of clinical research subjectsusing routine administrative data could be an ex-tremely useful way to obtain extended follow-up inclinical trials. Although it is conceptually simple tofollow up patients by linking research databases withnational administrative records, this is hugely diffi-cult to accomplish in the United States. Our health-care system is fragmented, with multiple payers;many patients are uninsured; Americans are obsessedwith privacy and distrust the government and largecorporations; and regulations designed to protectparticipants in high-risk clinical interventions havebeen applied indiscriminately to low-risk researchstudies.

SEE PAGE 2101

Other countries, such as Denmark, have universalhealthcare systems and different attitudes aboutprivacy and use of personal data for research pur-poses. In this issue of the Journal, Danish researchershighlight the value of their country’s willingness toallow linkage of multiple healthcare and administra-tive data resources and assess the long-term out-comes of patients treated for an acute MI (5).

Pederson and associates nicely document the lateoutcomes of primary percutaneous coronary inter-vention (PCI) for acute MI (5). The survival curveclearly shows 2 distinct phases, indicated by a clearbreak in the slope of the curve at about 6 months offollow-up. The early high-risk period is almost

entirely attributable to cardiac mortality, which is notsurprising in a cohort of patients who have had anacute MI. Successful primary PCI reduces but does noteliminate the mortality of an acute MI. More subtly,there is a treatment selection bias for primary PCI,since patients with a serious noncardiac disease areunlikely to be chosen, which reduces the risk of anearly noncardiac death.

After about 6 months, the survival curve flattensout as the early risk phase of the acute MI passes, andthe later-phase steady-state risk becomes evident. Inthis later phase, cardiac mortality appears to be onlyhalf of total mortality: patients with an acute MIremain vulnerable to noncardiac disease, and some ofthe same factors that put them at risk for an MI alsoincrease their risk for noncardiac death. Diabetes, forinstance, is a strong predictor of late mortality, onlysome of which is cardiac. Lung disease and cancerdue to smoking also pose long-term risks to survivorsof an acute MI. The reduction in mortality from pri-mary PCI can only be a short-term success, and in thelong term, other forces of mortality will come to thefore.

One implication of these observations is that wecannot rest on our laurels after successful treatmentof an acute MI. We need to recognize the factors, bothcardiac and noncardiac, that pose the greatest risk topatients who survive an MI and initiate the therapiesand behavior changes that will reduce the risk of latemortality. Long-term results matter, even for acuteillnesses and short-term therapies. We need todevelop methods to obtain long-term follow-up effi-ciently so we can document outcomes and identifyoptimal strategies to reduce long-term risk.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Mark A. Hlatky, Stanford University School of Medi-cine, HRP Redwood Building, Room 150, Stanford,California 94305-5405. E-mail: hlatky@stanford.edu.

RE F E RENCE S

1. Canner PL, Berge KG, Wenger NK, et al. Fifteenyear mortality in Coronary Drug Project patients:long-term benefit with niacin. J Am Coll Cardiol1986;8:1245–55.

2. Baigent C, Collins R, Appleby P, Parish S,Sleight P, Peto R, on behalf of the ISIS-2 (SecondInternational Study of Infarct Survival) Collabo-rative Group. ISIS-2: 10 year survival amongpatients with suspected acute myocardial in-farction in randomised comparison of intravenous

streptokinase, oral aspirin, both, or neither. Lancet1998;316:1337–43.

3. FranzosiMG, Santoro E, De Vita C, et al., on behalfof the GISSI Investigators. Ten-year follow-up of thefirst mega-trial testing thrombolytic therapy in pa-tientswith acutemyocardial infarction: results of theGruppo Italiano per lo Studio della Sopravvivenzanell’Infarto-1 Study. Circulation 1998;98:2659–65.

4. Hlatky MA, Ray RM, Burwen DR, et al. Use ofMedicare data to identify coronary heart disease

outcomes in the Women’s Health Initiative. CircCardiovasc Qual Outcomes 2014;7:157–62.

5. Pedersen F, Butrymovich V, Kelbæk H, et al.Short- and long-term cause of death in patientstreated with primary PCI for STEMI. J Am CollCardiol 2014;64:2101–8.

KEY WORDS coronary artery disease, follow-up studies, percutaneous coronary intervention,selection bias, stent(s)