Eur Heart J-1996-Flack-16-20.pdf

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Adherence to anti-hypertensive therapy 17

pressure-lowering medication' '2 '13 ' , although somestudies have not confirmed this observation. Interest-ingly, older patients tend to discontinue treatmentbecause of adverse effects, whereas younger patients quittheir medications because of improvement undertherapy1'41 . Importantly, physicians fare poorly whenthey attempt to subjectively estimate therapeuticcompliance"5 .

Side effects that are perceived as secondaryto anti-hypertensive medication have correlated withnon-adherence to anti-hypertensive drug regimens inseveral previous studies110 '16 '171 . Thus, the magnitude ofexpected medication side effects should be an importantconsideration when prescribing anti-hypertensive drugtherapy. It can be difficult to know, at least with anydegree of confidence, if side effects occurring duringanti-hypertensive drug therapy are actually caused bythe prescribed medication(s) because there is overlapbetween clinical symptoms attributable to hypertensionand drug-induced side effects. In addition, perceived sideeffects are more likely to occur at the beginning of

therapy and tend to decrease in frequency over time,probably because of psychological rather than pharma-cological factors1'81.

Headaches can occur either as a consequenceof hypertension or as a side effect of certain anti-hypertensive medications, particularly those belongingto the vasodilator class. In the Treatment of MildHypertension Study (TOMHS) (average pre-treatmentblood pressure 140/91 mm Hg ), d rug-treated hyper-tensives had fewer headaches than hypertensives takingplacebo, even though both groups had averageblood pressure levels within the normal range(< 140/90 mrnHg )'"1 . This finding suggests that even

patients with stage I or 'mild' hypertension are sympto-matic and that low to moderate doses of anti-hypertensive drug therapy can lessen the burden of thesesymptoms.

The widespread misperception, held byboth patients and physicians, that hypertensives areinfrequently symptomatic probably contributes to thera-peutic non-compliance, particularly among drug-treatedhypertensives who have elevated blood pressure. In such

Table 1 Factors influencing adherence to anti-hypertensive drug therapy

Increased D ecreased

Higher blood pressure levelFemale genderHigher educationHigher incomeMarriedCulture

Complex drug regimenSide effectsHigh costRapid blood pressure loweringCigaret te smokingYounger ageHigh salt useLong-term treatmentPerceived barriers to treatmentExcessive alcohol intakeCulture

patients, blood pressure-related symptoms (i.e. head-ache, poor exercise tolerance, fatigue) are often blamedon their anti-hypertensive medications. Thus, the patientmay be reluctant to take the necessary higher doses ofmedication or additional medications to achieve bloodpressure control, because they have mistakenly blamedtheir blood pressure-related symptoms on their anti-hypertensive medications.

Does adherence influence bloodpressure control or risk of adverse

clinical events?

At least one way that non-compliance to anti-hypertensive drug therapy influences patient outcomeshas been through worsened blood pressure control.Indeed, a substantial body of data has accruedregarding the effect of adherence to anti-hypertensivemedication on blood pressure control. Black and co-workers'201 reported data from the Systolic Hypertension

in the Elderly Program (SHEP) pilot study showingthat >80% compliance, as assessed by pill count, wasassociated with a greater probability of achieving targetsystolic blood pressure reductions both in the active(82-8% vs 61-5%) and placebo (34-6% vs 16-7%) treat-ment groups. The finding of a relationship betweensystolic blood pressure response and therapeuticcompliance in the placebo gro up suggests that individualattributes positively associated with adherence to drugtherapy independently contribute to blood pressurelowering. In this study men and women were equallycompliant. A study by Nelson and colleagues'101 alsodocumented a positive correlation between diastolic

blood pressure control and adherence to drug therapy ina relatively poor urban sample of hypertensive patients.In addition, 54% of patients deemed compliant,comp ared with 29% of non-co mpliant patients, reportedmissing no medication doses during the previous4 weeks. Similarly, Hershey and coworkers'2'1 found thathypertensive patien ts attending a university-based clinic,who reported total adherence to their regimen of bloodpressure medications, achieved blood pressure controlmore often than those reporting less compliance (75% vs53%, P<00l).

Recently reported data'22 1 from a hypertensiveMedicaid population found that therapeutic non-

compliance was associated with higher total healthcarecosts. In this study, 86% of newly initiated anti-hypertensive drug therapy was interrupted or dis-continued du ring the first year, resulting in total medicalcosts that were US$873/patient higher during that sameyear compared with hypertensives without documentednon-compliance. The increased costs were primarily dueto higher inpatient hospital expenditures totallingUS$637/patient. Thus, in aggregate, these data suggest alink between the level of blood pressure control andcompliance with anti-hypertensive drug therapy, aswell as an immediate correlation of therapeutic non-compliance with increased healthcare expenditure.

Eur Heart J, Vol. 17 (Supplement A), 1996



18 J. M. Flack et al.

What is the relationship of bloodpressure control to adverse clinical

outcomes?

In the United States sequential national surveys haveshown that 'hypertension awareness' treatment andblood pressure control have improved steadily over

the last several decades

[23]

. Nevertheless, the absoluteproportion of hypertensives who had achieved bloodpressure normalization during the most recent NationalHealth and Nutrition Survey III (NHANES III) during1988-1991 was quite low. Only 2 1% of free-livinghypertensives in the United States achieved a bloodpressure level of < 140/90 mm Hg , althou gh a more im-pressive 55% had blood pressure levels < 160/95 mmHg.The NHANES I Epidemiological Follow-Up Study(Table 2) found an 82% and 97% higher 9-year age- andsmoking-adjusted risk of mortality in drug-treatedhypertensive white men and women, respectively,who h ad not achieved b lood pressure control (< 160/95 mm Hg), compared with same gender norm o-

tensives1241

. On the other hand, excess mortality amongdrug-treated hypertensives with 'controlled' hyper-tension (< 160/95 mmHg) was somewhat less being only36% and 30% higher in white men and women, respec-tively, compared with same gender normotensives.

A major reason for the inability to achieve amortality risk in drug-treated hypertensives comparablewith that in normotensives has been the problem inpersistent blood pressure elevations despite pharmaco-therapy. Observations made by Flack and Wiistl" 1

are also consistent with this line of reasoning. Theydocumented higher blood pressures in middle-agedAfrican-American hypertensives than in age-, body mass

index- and gender-matched normotensives (men 139/88vs 132/83 m m Hg ; wo men 139/86 vs 129/79 m mH g).Stated another way, these hypertensives never achievedthe lower blood pressure levels of same gender normo-tensives who were the same age and of similar body size.Thus, poor blood pressure control, which occurs in nosmall consequence because of poor adherence to long-term anti-hypertensive drug therapy, plays a substantialrole in the development of increased risk of excess

Table 2 Relative risk of death over 9 years in whiteadults aged 50 years and older epidemiological follow-up

survey. Adapted with permission from Havlik et aU24 J

)

H y p e r t e n s i o n s ta tusM en Women

( n = 2 5 4 9 ) ( n = 2 8 2 8 )

U n a w a r e , blood pressure not e levated* 10 10Aware, blo od pressure not e levated, on

med ication 1 -36 1-30Aware, bloo d pressu re elevated, no med ication 1-75 1-68Aware, bloo d press ure elevated, on med ication 1-82 1-97

•Reference group .Relative risk of 1 -36 correspo nds to a 36% higher r isk of morta l i tyc o m p a r e d with the reference g roup .

mortality experienced by drug-treated hypertensive menand women.

The Treatment of Mild HypertensionStudy TOMHS)

TOMHS was a multicentre, randomized, placebo-controlled clinical trial involving 902 men and womenaged 45-69 years, most of whom had so-called 'mild'or Stage I hypertension. The range of pre-treatmentdiastolic blood pressure was 90-99 mmHg among thosenot taking medication at baseline (39-1%), while dia-stolic blood pressure ranged between 85 and 99 mm Hgamong the larger group (60-9%) who were taking medi-cation at baseline. Blood pressure averaged 140/91 mmHgat randomization 3'191 . Participants were randomized tolifestyle modification (weight loss, salt and alcoholrestriction, physical activity increase) or placebo plusone of five active drug therapies. Active drug treatmentsincluded chlortha lidone (15 mg . day "1), acebutolol

(400 mg . day~')> amlodipine (5 m g. da y~ ') enalapril(5 mg . da y"') and doxazosin (2 mg . day" 1)- Analysesrelating to hard clinical events, such as MI and stroke,were not drug specific but were aggregate contrasts of allactive drug groups combined (drug plus lifestylemodification) compared with placebo (lifestyle modifi-cation only). Follow -up averaged 4-4 years.

Blood pressure was lowered an average of -15-9/— 12 3 mm Hg and —9-1/—8-6 mm Hg in the combineddrug and placebo treatment groups, respectively.The betw een-gro up difference of 6-8/3-7 mm Hg washighly significant both for systolic and diastolic bloodpressure (/3<0-0001). After 48 months of follow-up,

blood p ressure averaged 126-7/79-4 mm Hg and 132-6/81-9 mm Hg in the com bined drug and placebo treat-ment groups, respectively. Thus, both groups attainedsystolic and diastolic blood pressure levels that werewithin the 'n orm al' range (< 140/90 mm Hg). There wasno difference in diastolic bloo d pressure lowering am ongthe five drug groups. However, average systolic bloodpressure lowering during follow-up was greater withchlorthalidone (—17-7 mm Hg) comp ared with amlo -dipine (—15-6 mm Hg ), do xazosin (—14-2 mm Hg) andenalapril (—14-7 m mH g). T he average redu ction insystolic blood pressure was significantly greater withacebutolol (—17-0 mm Hg ) com pared with dox azosin(-14-2 mmHg) P<00\) and with chlorthalidone

compared with doxazosin and enalapril (/><0-01).Furthermore, at 48 m onths all drug treatments, with theexception of enalapril, had significantly lowered bloodpressure compared with placebo P<00\).

Table 3 displays long-term adherence dataaccording to drug treatment group. Long-term adher-ence was defined as the proportion of participantsrandomized to each drug who remained on their initialtreatment assignment (monotherapy) at 48 months. Onlyamlodipine (82-5%) and acebutolol (77-8%) demon-strated significantly greater long-term drug adherencethan placebo (58-5%) (both contrasts, P<00l). Further-




Adherence to anti-hypertensive therapy 19

Table 3 Long-term 48-month) adherence to anti-hypertensive drug monotherapies in the Treatment of MildHypertension Study TOM HS). Percentage values refer to the proportion of participants initially assigned to eachdrug group that remained on only that drug at 48 m onths

Acebutolol* Am lodipi ne ' Chlor thal idone* Doxazosin* Enalapril Placebo(n = 126) (n = l 14) (n= 117 ) (n= 121 ) (n = 119) (n= 207 )

On initial treatment (%)

Withdrawn (%)Prescribed other blood pressure

medication (%)

77-8

7-9

14-3

82-5

6 1

11-4

67-5

14-5

17 9

6 6 1

12-4

21-5

6 81

11-8

2 2

58-5

8-7

32-9

*/"<001 for placebo vs acebutolol and amlodipine; chlorthalidone and doxazosin vs amlodipine.

more, among the five drug groups, greater long-termadherence was documented for participants takingamlodipine compared with participants taking eitherchlorthalidone or doxazosin ( P <0 01 for both contrasts).

Major coronary heart disease and cardiovasculardisease events were 36% lower in the combined drugtreatment group compared with the placebo group

(4-49% vs 6-84%, P=0\5). When other clinical eventswere also considered, the event rate was 34% lower inthe combined drug treatment group compared with theplacebo gro up (11-08% vs 16-24%, P= 0-0 3).

Implications of the TOMHS data

The TOMHS study suggests that there are long-termdifferences in adherence to anti-hypertensive drugtherapy in patients with mostly 'mild' or Stage I hyper-tension. Adherence to any drug therapy is, minimally, aresult of the combined forces of blood pressure-lowering

efficacy and patient tolerability of the prescribed drug.Patient tolerability will, to no small degree, relate toperceived side effects. Drugs that result in a highdegree of therapeutic non-adherence can increase totalhealthcare costs, because patients taking these drugs willhave a greater number of clinic visits triggered byperceived side effects. Conversely, drugs with greaterlong-term tolerability will minimize overall healthcarecosts because of fewer clinic visits for perceived medi-cation side effects. Furthermore, Elliott125) performed aninteresting analysis in a tertiary Hypertension Clinicof the costs associated with discontinuing 'preferredtherapy' with diuretics and (J-blockers (as recommendedin the Fifth Report of the Joint National Committee on

Detection, Evaluation and Treatment of High BloodPressure [JNC-V]) and switching to alternative drugtreatments. During the ensuing 12 mo nths after thetherapeu tic switch was made, SI333 in total medical carecosts were generated; these patients underwent twoadditional clinic visits (5-9 vs 4 1 ; f< 0 0 1 ) with m uch ofthe additional monetary expenditure going towardsblood pressure monitoring and laboratory costs. Thus,in spite of the low acquisition costs of 'preferred' anti-hypertensive drug therapies, there is a sizable financialcost when patients (such as those experiencing sideeffects) are switched to alternative therapies. Drug

acquisition costs must be, therefore, considered in thecontext of how they impact upon the non-drug portionof the healthcare expenditure equation.

Most anti-hypertensive drugs will ultimatelylower blood pressure to a similar degree. In addition,when differences in blood pressure lowering occur, theycan often be overcome by upward titration of a given

medication. Thus, selection of initial anti-hypertensivemonotherapy usually hinges on issues, such as co-existing medical conditions and side effects, rather thanblood pressure-lowering efficacy. On the other hand,clinic visits often occur with upward titration of anti-hypertensive drugs, thus escalating the overall cost ofmedical care.

No authoritative expert panel has yet to recom-mend that blood pressure should be lowered well intothe normal range (< 140/90 mmHg) to achieve optimalattenuation of blood pressure-related morbid and fatalclinical events. Yet, one interpretation of the TOMHSdata would be that the lower the blood pressure the

greater the reduction in risk for blood pressure-relatedsequelae.

Another important issue is related to drug half

lives. Missed medication doses are inevitable in manydrug-treated hypertensives. Drugs with long intrinsichalf-lives (see Table 4) provide both a more gradualonset of action (and probably more gradual onset ofblood pressure lowering) and a slower offset of action.The slow offset of action provides greater therapeuticcoverage when medication doses are missed thanoccurs with drugs with shorter half-lives. Thus, whenmedication doses are missed there will be less lossof blood pressure control. Two TOMHS drugs withvery long intrinsic half-lives were chlorthalidone andamlodipine.

Table 4 Relative length of drug half-lives, or duration ofaction of, among com monly used drug classes

DiureticsACE inhibi torsCalcium antagonistsAlphai antagonistsP-blockers

ChJorthal idoneQuinapri lAmlod ip ineDoxazosinAtenolol

> Hydrochlorothiazide>Cap top r i l>Felodipine>Terazosin>Proprano lo l

ACE=angiotensin convert ing enzyme.

Eur Hea rt J, Vol. 17 (Supplem ent A ), 1996



20 J. M. Flack et al.

Conclusion

Long-term adherence to anti-hypertensive drug therapyhas proven benefits, even for persons with 'mild' or StageI hypertension. Avoiding rapid reduction in bloodpressure and using drugs with long intrinsic half-liveswill provide maximum therapeutic coverage whenmedication doses are missed. To avoid over treating

patients, unless the initial blood pressure elevation issevere, anti-hypertensive drugs should be titrated at nomore frequent intervals than every 4-8 weeks. Finally,the therapeutic goal in most hypertensive patientsshould be gradual normalization of blood pressure(< 140/90 mmH g).

The authors wish to thank Ms Michelle Coe for typing thismanuscript and for her very much appreciated time andeffort.

References[1] MacMahon S, Peto R, Cutler J et al. Blood pressure, stroke

and coronary heart disease. Lancet 1990; 335: 765-74.[2] Flack JM, Neaton JD, Daniels B, Esunge P. Ethnicity and

renal disease: lessons from Multiple Risk Factor InterventionTrial and the Treatment of Mild Hypertension Study. Am JKidney Dis 1993; 21 (Suppl 1): 31-40.

[3] Neaton JD, Grimm RH Jr, Prineas RJ et al. Treatment ofMild Hypertension Study (TOMHS) final results. J Am MedAssoc 1993; 270: 713-24.

[4] Collins R, Peto R. Blood pressure, stroke, and coronary heartdisease. Part 2. Short-term reductions in blood pressure:overview of randomised drug trials in their epidemiologicalcontext. Lancet 1990; 335: 827-38.

[5] Hamilton M, Thompson EN, Wisiewski TKM. The role ofblood pressure control in preventing complication ofhypertension. Lancet 1964; 1: 235-8.

[6] SHEP Cooperative Research Group. Prevention of stroke by

antihypertensive drug treatment in older persons with isolatedsystolic hypertension. J Am Med Assoc 1991; 265: 3255-64.

[7] Caldwell JR, Cobb S, Dowling MD, De Jongh D. The dropoutproblem in antihypertensive therapy. J Chronic Dis 1970; 22:579-92.

[8] Degoulet P, Menard J, Vu HA et al. Factors predictingattendance at clinic and blood pressure control in hypertensivepatients. Br Med J 1983; 287: 88-93.

[9] Haynes R B. Manag eme nt of patient com pliance in thetreatment of hypertension. Report of the NHLBI WorkingGroup. Hypertension 1982; 4: 415-23.

[10] Nelson EC, Stason WB, N eutra RR, Solomons HS.Identification of the noncompliant hypertensive patient. PrevMed 1980; 9: 504-17.

[11] Flack JM, Wiist WO. Cardiovascular risk factor prevalencein African-Am erican adu lt SCTeenees of a church-basedcholesterol education program: the Northeast Oklahoma CityCholesterol Education Program (NEOCEP). J Ethnicity Dis1991; 1:78 90.

[12] O'Brian Smith E, Curb JD, Hardy RJ, Hawkins CM, TyrolerHA. Clinic attendance in the hypertension detection andfollow-up program. Hypertension 1982; 4: 710-5.

[13] Daniels DE, Rene AA, Daniels VR. Race: an explanation of

patient compliance — fact or fiction? J Natl Med Assoc 1994;86: 20-5.[14] Roth K, Jeck T, Edmonds D, Bachmann L, Vetter W. Der

Umgang mit Medikamenten: Erfahrungen mit einemDiaprogramm und Patientenbefragung. Schweiz RundschauMed(PRASIX) 1989; 43: 1187-91.

[15] Norell SE. Accuracy of patient interviews and estimates byclinical staff in determining medication compliance. Soc SciMed 1981; 15E: 57-61.

[16] Latiolasis CJ, Berry CC. Misuse of prescription medicationsby outpatients. Drug Intel Clin Pharm 1969; 3: 270-7.

[17]Sackett DL, Haynes RB, Gibson ES et al. Randomizedclinical trial of strategies for improving medication compliancein primary hypertension. Lancet 1975; 1: 1205—7.

[18] Edmonds D, Greminger P, Vetter W, Baumgart P, Vetter H.The neglected time factor and antihypertensive therapy. Apitfall in evaluating side effects in a cross-over study. PostgradMed J 1988; 83: 40-5.

[19] The Treatment of Mild H ypertension R esearch G roup(TOMHS). A randomized, placebo-controlled trial of anutritional-hygienic regimen along with various drug mono-therapies. Arch Intern Med 1991; 151: 1413-23.

[20] Black D M , Brand RJ, Greenlick M , Hughes G , Smith J.Compliance to treatment for hypertension in elderly patients:the SHEP pilot study. Systolic Hypertension in the ElderlyProgram. J Gerontol 1987; 42: 552-7.

[21] Hershey JC, Morton BG, Davis JB et al. Patient compliancewith antihypertensive medication. Am J Public Health 1980;70: 1081-9.

[22] McCombs JS, Nichol MB, Newman CM, Sclar DA. The costsof interrupting antihypertensive drug therapy in a Medicaidpopulation. Med Care 1994; 32: 214-26.

[23] The Fifth Repo rt of the Joint N ational C omm ittee on

Detection, Evaluation and Treatment of High Blood Pressure.National High Blood Pressure Education Program. NationalInstitutes of Health. National Heart, Lung and BloodInstitute. NIH Publication January 1993; No. 93: 1088.

[24] Havlik RJ, LaCroix A Z, Kleinman JC, Ingram DD , HarrisT, Cornoni-Huntley J. Antihypertensive drug therapy andsurvival by treatm ent status in a na tional survey. Hypertension1989; 13 (Suppl I): 1 28 32.

[25] Elliott WJ. Costs associated with changing antihypertensivedrug monotherapy: 'preferred' vs 'alternative' therapy. Am JHypertens 1995; 8: 80A.


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