Too Little, Too Late?A treatment for heart attackmay be dangerously underused

Athrombolytic agent can save your life if you suÝer a heart attack. But in the U.S., if you are old or

slow in getting to the hospital, yourchances of getting one may be dis-turbingly worse than youÕd like. Sur-veys show that only about a third of allheart attack patients receive a throm-bolyticÑroughly half of those who maybe eligible and far below the 85 percentmark attained in parts of the U.K.

Moreover, even patients who do get athrombolytic must often wait almostan hour and a half for it, a delay thatsigniÞcantly reduces the drugÕs eÝec-tiveness. By one estimate, 14,000 morelives might be saved annually if physi-cians used thrombolytics sooner andmore liberally. ÒI think the situation is improving, but itÕs woefully inade-quate,Ó remarks Andrew J. Doorey ofthe Medical Center of Delaware.

Streptokinase, tissue plasminogenactivator (TPA) and other thrombolyt-ics work by dissolving the blood clots

that block coronary arteries and causeheart attacks. At least one study foundthat administering these agents withinan hour of the onset of chest pain cutmortality by 90 percent, although mostestimates put the beneÞt at a moremodest 50 percent. Unfortunately, thatgain decreases when treatment is post-poned, and most patients do not reachan emergency room until at least fourhours after their heart attack begins.Still, thrombolytics reduce mortality by30 percent when given within the Þrstsix hours and by about 15 percent be-tween the sixth and 12th hours.

The drawback of the drugs is thatthey promote bleeding and raise theodds of a potentially fatal stroke froman intracranial hemorrhage. Physicianshave therefore tended to prescribe clot-busters only for the minority of pa-tients who oÝered the best ratio ofbeneÞts to risks. ÒInterfering with thebodyÕs blood-clotting mechanism is aserious business,Ó cautions H. VernonAnderson of the University of TexasHealth Science Center. ÒYou want to bevery, very careful.Ó

Last fall in the New England Journal

of Medicine, Anderson and James T.Willerson of the Texas Heart Institute

SCIENTIFIC AMERICAN February 1994 21

phenomenon the existence of which Aleksander F. Andreev of the Institute for PhysicalProblems in Moscow proposed in 1964. At the super-semi interface, an electron fromthe well enters a superconductor to form a Cooper pair. As it does so, it leaves behinda positively charged “hole” in the sea of electrons in the well. The hole is a kind of mir-ror image of the electron. According to theory, the hole moves along a time-reversedpath of the original electron—that is, the hole travels to the other side of the well.

Once the hole reaches the other interface, it breaks up a Cooper pair in the othersuperconducting contact. One of the Cooper electrons destroys the hole; the othertakes up this annihilation energy and shoots across the well back to the other side.The process can repeat once this electron moves across the interface and forms aCooper pair. In theory, the cycle can go on forever.

More startling was the effect’s dependence on an external magnetic field. Kroemerfound that a rising magnetic field caused resistance to increase episodically instead ofsmoothly. The jerkiness or bumpiness of the increasing resistance should involve afundamental parameter—the flux quantum. The flux quantum dictates that bundlesof magnetic-field lines penetrating a sample must take on a particular, discrete value.Instead, Kroemer reports, the measured value is smaller than the predicted one by afactor of four to five.

So far no good explanation exists for the oscillations. One speculation is that themagnetic-flux lines assume the form of a lattice as they penetrate the semiconductor.When the magnetic field is increased, the entire lattice shifts suddenly to accommo-date the new flux bundles. Kroemer plans to look for the effect in new samples beforesubmitting his results for publication.

Multiple Andreev reflections may be more common than previously observed. Forinstance, Alan W. Kleinsasser of the IBM Thomas J. Watson Research Center and hiscolleagues will report their observations of the reflections in a quantum structureknown as a tunnel junction. So whereas the birth of superconducting computers re-mains distant, investigators are finding plenty of excitement during the courtship pe-riod. Kroemer explains: “The physics for now takes precedence over the hypotheticalapplications.” —Philip Yam

Copyright 1994 Scientific American, Inc.

in Houston pointed out just how care-ful physicians have been. Thirty per-cent of all patients with heart attacksdo not get thrombolytic therapy, be-cause they arrive at the hospital morethan six hours after pain beginsÑtoolate, in the physicianÕs opinion. Becausethe elderly are at higher risk for stroke,15 percent are considered too old. An-other 25 percent are disqualiÞed be-cause their electrocardiograms do notsuggest that thrombolytic therapywould be helpful or because they seemprone to bleeding.

Are those criteria too conservative?The mortality for patients in clinicaltrials of thrombolytic therapy is typical-ly 2 to 10 percent; for those excludedfrom therapy, it is 15 to 30 percent.These alarming numbers suggest thatunless the risks of stroke and bleedingwould be far higher in the excludedgroupsÑan assumption that is espe-cially questionable for people who havejust arrived too lateÑthose patients,too, would beneÞt from thrombolytictherapy. Indeed, Anderson and Willer-son note that patients older than 75years were among the groups whomost beneÞted in clinical trials becausethey suÝer the most heart attacks.

Doorey believes perhaps as many as60 percent of all heart attack victimsmight qualify for thrombolytic therapy.

In the December 1992 issue of theJournal of the American Medical Associ-

ation, he, Eric L. Michelson of Hahne-mann University and Eric J. Topol of theCleveland Clinic Foundation tried to es-timate the potential impact of throm-bolytics. They concluded that expand-ed use of thrombolytics could triplethe number of lives saved, from 7,200to 21,950 annually.

Some advocates insist that com-pelling evidence for a broader use ofthrombolytics has existed since at least1988, when the Second InternationalStudy of Infarct Survival (ISIS-2) was re-leased. And many physicians in Europeseem to have concluded that aggressiveuse of thrombolytics is warranted. Areport in the Lancet last October claimsthat 85 percent of the heart attack pa-tients in some English hospitals re-ceived thrombolytics. It also points out,however, that regional hospitals variedgreatly in their practices: some hospi-tals used them only half that often.

ÒItÕs hard to have a handle on howmuch underutilization there is rightnow,Ó Topol argues. ÒIt appears to bemuch less than it was even a couple ofyears ago.Ó For patients older than 75years, he says, the rate of treatment hasjumped from 2 to 15 percent. Clinicalrecords from the Global Utilization ofStreptokinase and TPA for Occluded

Coronary Arteries (GUSTO) trial, whichhe supervised, suggested that ÒweÕretreating well over 80 percent of the ap-propriate patients.Ó

But Rory Collins of RadcliÝe InÞrm-ary at the Clinical Trial Service Unit ofthe University of Oxford dissents fromthat view. A leader of the ISIS-4 trial re-leased last November, Collins states thatÒthe U.S. was down in the lower endand the U.K. was up in the top endÓ infrequency of thrombolytic use. ÒI thinka lot of people are still uncertain aboutwhether they should be treating be-yond six hours,Ó he ventures. ÒThat ischanging, but it may be changing atdiÝerent rates in diÝerent places.Ó

Resistance to a therapy that may rou-tinely kill one or two out of every 1,000patients is understandable in a profes-sion trained to obey the motto primum

non nocere, ÒÞrst do no harm.Ó Emer-gency room internists must make rapiddecisions, on the basis of incompleteinformation, about the care of patientsthey have usually never seen before.They often weight their own experienceand that of their colleagues more heav-ily than clinical reportsÑwhich may ex-plain why the use of thrombolyticstends to be higher in hospitals thathave participated in clinical trials. Fearof liability also haunts some U.S. doc-tors, Doorey observes.

Better prescriptive guidelines maysoon appear in an upcoming paper inthe Lancet, in which Collins and his col-leagues make new recommendationsfor giving thrombolytic therapy to theelderly, people with histories of strokesand other categories of patients. ÒItputs together all the data on the sub-groups we have from the large-scaletrials, and it helps to guide treatmentfor individuals,Ó he says.

Quite aside from the issue of wheth-er more categories of patients shouldreceive thrombolytics, most experts be-lieve the therapy should be adminis-tered much more promptly. Studiesshow that from the time eligible pa-tients in the U.S. reach an emergencyroom, they must wait an average ofabout 85 minutes before their throm-bolytic therapy begins. That delay notonly lowers the beneÞt of the thrombo-lytics, at some hospitals it pushes pa-tients outside the accepted interval fortreatment.

Doorey and others are convinced thisÒdoor-to-needle timeÓ can and shouldbe cut to 20 minutes or less. To facili-tate the treatment, Òmost good hospi-tals are setting up multidisciplinary, in-terdepartmental teams,Ó Doorey ex-plains. ÒTheyÕre like the code-blue teamsthat treat trauma.Ó Some proponentshave suggested that thrombolytic ther-

22 SCIENTIFIC AMERICAN February 1994

HEART ATTACK PATIENTS can often beneÞt from getting clot-busting drugs, butmany who should be eligible may still not be receiving them.

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24 SCIENTIFIC AMERICAN February 1994

No Global Warming?CO2 readings on Mauna Loashow declining emissions

Since 1958, when researchers Þrstbegan to measure the rate atwhich carbon dioxide accumu-

lates in the atmosphere, they have seena consistent increase, perturbed onlyby minor seasonal ßuctuations. Then,about four years ago, the trend beganto waver. First a decline set in, followedby a plateau. After that, the decline re-sumedÑsharply. The event has left sci-entists, including those at the observa-tory on Mauna Loa in Hawaii, estab-lished by the late Harry Wexler to makethe measurements, wondering whathas happened.

Adding to the confusion, says CharlesD. Keeling of the University of Califor-nia at San Diego, who has operated agas analyzer at the observatory sinceits founding, is the fact that accumula-tion started to slump while the atmo-sphere was in the throes of an El Ni�o,a periodic shift in the circulation of

trade winds over the PaciÞc that aÝectsglobal weather and ocean currents. Dur-ing an El Ni�o, such as those of 1982Ð83 and 1986Ð87, atmospheric carbondioxide levels tend to rise faster thanthey do at other times. Keeling suspectsthat plants and soils release more car-bon dioxide during an El Ni�o becausewhen an Asian monsoon collapses, itcauses drought conditions. Whateverhas been reducing contributions of car-bon dioxide to the atmosphere hadsuch an impact that it entirely overrodethe eÝects of an El Ni�o.

Any number of events might havehad such climatic clout. Scientists caneliminate only one explanation imme-diately: the amount of carbon dioxidereleased from burning fossil fuels hasnot declined. The next most obviouscandidate is the June 1991 eruption ofMount Pinatubo in the Philippines. ÒThelink to the eruption is pretty specula-tive, but itÕs an attractive thing to thinkabout because of the coincidence intime,Ó says Ralph F. Keeling, CharlesKeelingÕs son and colleague at U.C.S.D.Of course, discovering whether the mys-tery source existed at land or at seawould narrow the search further. Un-fortunately, diÝerent tests have yieldedconßicting clues.

The ratio of carbon 13 to carbon 12in the atmosphere is one such mea-sure.. Photosynthesis on land prefersthe lighter isotope, whereas gas ex-change at sea discriminates only slight-ly between the two. ÒWe saw the ratiogo up, which would imply an increasedcarbon dioxide uptake by the terrestri-al biosphere,Ó says Pieter P. Tans of theNational Oceanic and Atmospheric Ad-ministration. ÒBut there could be con-

siderable error in that. It is very depen-dent on how good our calibration is.ÓIndeed, researchers measuring the car-bon isotope ratio have reported diÝer-ent results at various meetings over thepast year. Charles KeelingÕs data initial-ly indicated a large sink at sea. Aftercorrections were made to his calibra-tion, the results instead pointed to asink predominantly on land.

Oxygen emissions, on the other hand,support yet another idea. ÒItÕs fairlyclear that the land did not behave in atypical way for an El Ni�o, but the oxy-gen data suggest that maybe the oceansalso behaved strangely,Ó Ralph Keelingsays. Just as diÝerent ßavors of carbonisotopes are preferred by surf-and-turfreactions, so, too, varying proportionsof oxygen and carbon are engagedthrough the formation and consump-tion of organic matter. In addition, car-bon is quite reactive at sea, whereasoxygen is chemically neutral.

After considerable number crunch-ing, these facts taken together implythat if the sink were primarily on land,as the carbon isotope readings suggest,the change in the growth rate of atmo-spheric oxygen should be nearly equiv-alent to the recent change for carbondioxide. In fact, Ralph Keeling has ob-served oxygen emissions that roseabout twice as sharply as the rate bywhich carbon dioxide emissions fell af-ter the Pinatubo event. This Þnding in-dicates that signiÞcant changes tookplace in the oceans.

No matter where this carbon sink existed, scientists face the additionalchallenge of Þguring out how it hap-pened. There are several models basedon the fallout from Pinatubo that couldconceivably illustrate why carbon diox-ide emissions plummeted. Global cool-ing, measured in the low tropospherevia satellite, provides one compellingpathway. Such cooling could aÝect thebalance between photosynthesis andrespiration on land and could lead toan increased net uptake of carbon di-oxide in the oceans. ÒIt could cause a big, short-term jolt to the carbon balance. In 1994, if the temperaturecomes back to normal, we should getnormal carbon dioxide growth again,ÓTans notes.

So, is global warming on the way out?Tans does not think so. The decline inatmospheric carbon dioxide accumula-tion, he believes, is temporary. RalphKeeling agrees. ÒThat the carbon diox-ide growth will stay low is doubtful,Óhe says. ÒBut this is relevant at least inthe sense that it shows we donÕt reallyknow whatÕs happening with respect tothe most important man-made green-house gas.Ó ÑKristin Leutwyler

apy could be started in ambulances enroute to the hospital, but the evidencefor the beneÞt of this controversialpractice is uncertain.

ÒWeÕre talking about up to a 90 per-cent reduction in mortality from thebiggest killer in the Western world,ÓDoorey insists. ÒThat, I think, is thebiggest medical advance in this centuryoutside of antibiotics.Ó But it cannotlive up to that potential unless physi-cians use it more often. ÑJohn Rennie

ERUPTION of Mount Pinatubo in June 1991 may be responsible for lower carbondioxide emissions measured in the atmosphere since then.

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Copyright 1994 Scientific American, Inc.