The Paradoxical Significance of Headache in Hypertension

American Journal of Hypertension 29(9) September 2016 1109

Original article

Hypertension is a major cardiovascular risk factor and its treatment is efficient in lowering the risk of cardiovascular events1 While hypertension is mostly a silent disease it is frequently associated with headache or other neurological disorders namely migraine and tension-type headache23

The prognostic value of different subtypes of head-ache particularly migraine on cardiovascular outcomes is still controversial in the general population4 When first described in hypertension headache was initially associ-ated with malignant forms in an era of lack of antihyper-tensive treatment5 Nowadays headache remains a warning symptom but its prognostic significance remains largely unknown This question is of importance since headache often represents a concern both for the patient and for the physician when associated with hypertension particularly in the emergency department6

The aims of the present study were (i) to describe the char-acteristics and the clinical correlates of headache in a large cohort of hypertensive patients and (ii) to test the prognostic

value of this symptom for all-cause cardiovascular and stroke mortality This study benefited from a large cohort of hypertensive patients recruited in the 1970s with a detailed description of headache at baseline and followed for up to 30 years

METHODS

Patients

The Lyon OLD-HTA cohort has been previously described7ndash9 Briefly from January 1969 to December 1976 all patients consecutively referred to the Cardiology Department at the Louis Pradel Hospital (Lyon France) for a work-up of their hypertension were included in the present cohort In the70s hypertension was defined by an office blood pressure (BP) gt160 andor 95 mm Hg Figure 1 depicts the generation of the study cohort A small number of patients lost to follow-up or lacking information with

The Paradoxical Significance of Headache in HypertensionPierre-Yves Courand12 Michaeumll Serraille1 Nicolas Girerd3 Genevieve Demarquay4 Hugues Milon1 Pierre Lantelme12 and Brahim Harbaoui12

BACKGROUNDThe cardiovascular prognostic value of various types of headache particularly migraine in the general population remains controver-sial The aim of the present study was to assess their prognostic value for all-cause cardiovascular and stroke mortalities in hypertensive patients

METHODSA total of 1914 hypertensive individuals were first categorized accord-ing to the absence or presence of headache and thereafter according to the 3 subtypes of headache migraine daily headache and other headache

RESULTSMultiple regression analysis demonstrated that all headache types were predicted by gender (women) diastolic blood pressure absence of diabetes secondary hypertension and a trend for severe retinopa-thy After 30 years of follow-up 1076 deaths were observed 580 of whom were from cardiovascular cause and 97 from acute stroke In a

multivariable Cox model adjusted for major confounders patients hav-ing headache had a decreased risk for all-cause mortality (hazard ratio (HR) 082 95 confidence interval (CI) 073ndash093) and cardiovascular mortality (HR 080 95 CI 068ndash095) but not for stroke mortality (HR 100 95 CI 070ndash143) When considering only patients with headache ldquodaily headacherdquo had a nonsignificant better prognostic value for all-cause and cardiovascular mortality than ldquoother headacherdquo (HR 083 95 CI 068ndash101 HR 089 95 CI 069ndash116 respectively) and ldquomigrainerdquo (HR 085 95 CI 065ndash111 HR 078 95 CI 055ndash110 respectively)

CONCLUSIONPresence of nonspecific headache in hypertensive patients has a para-doxical significance in that it is associated with a high-risk profile but does not result in a worse prognosis over the long term

Keywords blood pressure headache hypertension hypertensive retin-opathy migraine mortality

doi101093ajhhpw041

Correspondence Pierre-Yves Courand (pycourandhotmailcom)

Initially submitted March 8 2016 date of first revision March 25 2016 accepted for publication April 5 2016 online publication April 19 2016

copy American Journal of Hypertension Ltd 2016 All rights reserved For Permissions please email journalspermissionsoupcom

1Cardiology Department European Society of Hypertension Excellence Center Hocircpital de la Croix-Rousse Hospices Civils de Lyon Lyon France 2Universiteacute de Lyon CREATIS CNRS UMR5220 Inserm U1044 INSA-Lyon Universiteacute Claude Bernard Lyon 1 Hospices Civils de Lyon Lyon France 3Inserm Centre drsquoInvestigations Cliniques 9501 amp U1116 Universiteacute de Lorraine Institut Lorrain du Cœur et des Vaisseaux Louis-Mathieu CHU de Nancy Vandœuvre-legraves-Nancy France 4Neurology Department Hocircpital de la Croix-Rousse Hospices Civils de Lyon Lyon France These authors contributed equally to this work

September

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1110 American Journal of Hypertension 29(9) September 2016

Courand et al

regard to the presence and characteristics of headache were excluded from the study resulting in a total of 1914 hyper-tensive patients being included in the present analysis Oral consent was obtained from every patient in accordance with French regulations prevailing at the time The study received approval of the Commission Nationale Informatique et Liberteacute (CNIL) Under French law as mentioned in sev-eral published technical notes in keeping with European directives10 only the approval of the CNIL is required for single-center observational usual care studies such as that performed herein The vital status query was approved by national authorities prior to data extraction by the Institut National de la Statistique et des Etudes Economiques

Baseline work-up

A special form was completed for every patient the con-tents of which included various morphometric characteris-tics risk factors for cardiovascular events (smoking status alcohol intake salt consumption etc) history of cardiovas-cular disease and current medication and symptoms

Smoking status was based on current tobacco consump-tion or stopped within the last 5 years BP was measured with a manual sphygmomanometer in supine position The considered systolic BP diastolic BP and pulse pressure were the mean of 6 measurements Twelve-lead electrocardiogram was performed in the supine position An ophthalmoscopic fundus examination of the right eye was performed after pharmacological pupil dilation to detect signs of hyperten-sive retinopathy Classification of hypertensive retinopathies was performed by 2 trained cardiologists according to the 4-grade classification of Keith Wagener and Barker largely used at that time11

An overnight fasting blood sample was drawn for hemo-gram and plasma measurements (electrolytes creatinine glucose and total cholesterol) Diabetes was retrospectively defined by either a fasting glucose ge126 gl (ge79 mmoll) on 2 separate occasions or a current use of antidiabetic medica-tion Renal function was estimated using the Modification of Diet in Renal Disease (MDRD) formula

Previous cardiovascular diseases included the history of heart failure (clinical or chest radiographic findings such as dyspnea edema cardiomegaly or pulmonary congestion)

coronary artery disease (clinical findings such as angina pectoris or myocardial infarction or Q wave on electrocar-diogram) peripheral arterial disease (walking impairment or pain at rest) and stroke (clinical findings) Target organ damage was defined according to the following electri-cal left ventricular hypertrophy in case of a Sokolow index gt35 mV presence of albuminuria if gt300 mgday and hypertensive retinopathy (including all grades from 1 to 4 or only advanced retinopathy including grades 3 and 4)2 Malignant hypertension was defined according to the pres-ence of grade 3 or 4 hypertensive retinopathy and diastolic BP gt130 mm Hg2

Assessment of headache

All patients were carefully questioned at baseline by 2 trained physicians regarding their history of headaches The first question was ldquoDo you often experience headacherdquo (ie at least twice during the past year) If the answer was ldquoyesrdquo the patient was categorized as having headache and had to answer the following standardized items (i) the local-ization of the headache (unilateral or bilateral) (ii) the con-comitant presence of other symptoms including nausea and vomiting (iii) the intensity of the headache (severe or mild) and (iv) the frequency of headache per week The following classification of headaches was retained as derived from the International Headache Society (IHS) diagnostic criteria3

1 Migraine inclusion criteria required at least 2 of the fol-lowing itemsmdashsevereunilateralassociated with nausea or vomiting Exclusion criteria mainly consisted in the presence of daily headache

2 Daily headache patients with daily symptoms3 Other headache patients with headache not included in

the previous 2 categories

Hence patients from our cohort were divided into 4 sub-groups no headache (NH) migraine (M) daily headache (DH) and other headache (OH)

Assessment of outcomes

Deaths at 30 years of follow-up were obtained from the Reacutepertoire National drsquoIdentification des Personnes Physiques (RNIPP a directory maintained by the Institut National de la Statistique et des Etudes Economiques INSEE) Causes of death were coded from the death certificates as provided by INSERM SC8 according to the International Classification of Diseases Ninth Revision

The end points used in this study were all-cause deaths (cardiovascular and noncardiovascular including sudden death) cardiovascular deaths (from cerebrovascular dis-ease myocardial infarction or heart failure) and stroke deaths as classified by the French national CeacutepiDC (Centre drsquoEpideacutemiologie sur les Causes Meacutedicales de Deacutecegraves)12

Statistical analyses

Continuous variables with near-normal distributions are expressed as mean plusmn SD Continuous variables with skewed

Figure 1 Flowchart summarizing the generation of the study cohort

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Headache and Hypertension

distributions are expressed as median (interquartile range) while categorical variables are expressed as percentages

Appropriate tests (ANOVA or χ2) were used to compare the characteristics of the different subgroups Two types of comparisons were performed according to (i) the presence vs absence of headache and (ii) the 3 subtypes of headache defined above (DH OH and M) as opposed to patients with no headache complaint (NH)

The predictors of headache at baseline were assessed by multiple logistic regression according to (i) the presence vs absence of headache and (ii) the 3 subtypes of headache defined above (DH OH and M) as opposed to patients with no headache history (NH)

The prognostic value of headache in terms of all-cause car-diovascular and stroke deaths was first estimated by KaplanndashMeier survival curves (log-rank statistic) according to the presence vs absence and subtypes of headache The prognos-tic value of subtypes of headache was represented with Cox regression curves adjusted for age as these subgroups display significant differences in terms of age The same 2 modalities (presence vs absence and subtypes of headache) were also tested by multivariable Cox regression (χ2 statistic) using 2 models model 1 was adjusted for age sex systolic BP diastolic BP diabetes total cholesterol smoking status MDRD antihy-pertensive treatment previous cardiovascular disease essential hypertension and body mass index model 2 was adjusted for all variables used in model 1 plus hypertensive retinopathy electri-cal left ventricular hypertrophy and albuminuria A headache-by-time interaction was introduced into the multivariable Cox regression model to test the proportional hazards hypothesis This interaction was not statistically significant with regard to all-cause or cardiovascular death at 30 years

Two sensitivity analyses were repeated with the same Cox regression multivariable models after excluding 59 patients who died during the first year of follow-up and also after exclusion of 93 patients with malignant hypertension

The analyses were performed using the SPSS 2000 soft-ware package (SPSS Chicago USA) A P value lt005 was considered as statistically significant

RESULTS

Patient baseline characteristics and outcomes

The cohort was characterized by high BP levels and more than one-fifth of patients had a previous cardiovascular disease (Table 1) The most frequent etiologies were renal parenchymal disease (78) and renal artery stenosis (37) A history of headache was present in 556 (N = 1064) of the entire cohort Headaches were more frequent in women nonsmokers and nondiabetics Patients with headache had a more severe risk profile than patients without headache in terms of BP levels estimated glomerular filtration rate and hypertensive retinopathy (Table 1) they were also character-ized by a higher rate of secondary forms Predefined head-ache subgroups were distributed as follows M (193 patients) DH (268 patients) and OH (603 patients) while 850 patients did not report any history of headache (NH) Age gender smoking status systolic BP diastolic BP and estimated glomerular filtration rate significantly differed between

subgroups (Supplementary Table S1) Again the risk profile worsened with an increasing frequency of headache (DH) in comparison with the other 2 subgroups (M and OH)

Multiple regression analysis revealed that all headache types were predicted by gender (women) diastolic BP the absence of diabetes secondary hypertension and a trend for severe retinopathy (Table 2) Further analysis of the 3 sub-groups of headache demonstrated that all were associated with diastolic BP while only DH was a predictor of severe hypertensive retinopathy (Table 2) DH also remained an independent predictor of severe hypertensive retinopathy (odds ratio 174 95 confidence interval (CI) 120ndash252 Supplementary Table S2) even after exclusion of patients with malignant hypertension (odds ratio 205 95 CI 134ndash313)

After a 30-year follow-up period 1076 deaths were recorded 580 of whom were from cardiovascular causes including 97 acute strokes

Survival analysis

According to the presenceabsence of headache As shown by the KaplanndashMeier curves (Figure 2) after 30 years of follow-up the survival rates decreased in hypertensive patients without headache both for all-cause (P = 0008) and cardiovascular mortality (P = 0044) With regard to stroke mortality the 2 survival curves were relatively similar (P = 0812 Figure 2)

In multivariable Cox regression model 1 comparatively to patients without headache those with headache had a lower risk for all-cause mortality (hazard ratio (HR) 082 95 CI 073ndash093) and cardiovascular mortality (HR 080 95 CI 068ndash095) but not for stroke mortality (HR 100 95 CI 070ndash143 Table 3) Results were similar for multivariable Cox regression model 2 (Table 3)

According to the 4 headache subgroups (DH M OH and NH) As shown by the Cox regression curves adjusted for age (Figure 3) after 30 years of follow-up patients with M OH and DH exhibited superimposable outcomes for all-cause cardiovascular and stroke mortality (P = 0465 P = 0684 and P = 0865 respectively) For purposes of clarity the survival curves for patients with NH are not represented in Figure 3 NH patients had worse outcome for all-cause and only a trend for cardiovascular mortality (P = 0029 and P = 0226 respectively) while survival curves of the 4 subgroups were superimposable for stroke mortality (P = 0902)

In multivariable Cox regression model 1 patients with DH exhibited a nonsignificant better prognostic value than those with M and OH with respect to all-cause and cardiovascular mortality (Table 3) In multivariable Cox regression model 2 (which included further adjustment for hypertensive retin-opathy electrical left ventricular hypertrophy and albumi-nuria) the results remained relatively similar (Table 3)

Sensitivity analyses

After exclusion of patients deceased during the first year of follow-up (N = 59) the prognostic value of headache in the 2 multivariable Cox regression models remained similar

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Courand et al

to that found in the whole cohort patients with headache in comparison with those without headache had a decreased risk for all-cause mortality and cardiovascular mortality but not for stroke mortality in both models (Supplementary Table S3) In the second sensitivity analysis in which patients with criteria for malignant hypertension (N = 93) were excluded the results were relatively similar for both multi-variable Cox regression models (Supplementary Table S4)

DISCUSSION

The present study was carried out on a large cohort of hypertensive individuals with a long follow-up period and a detailed characterization of their headache A paradoxi-cal significance of headache was observed since despite a worse risk profile at baseline it carried a good prognostic significance over the long term Thus headache should be

Table 1 Baseline characteristics of the whole cohort and according to the presence of headache

Characteristics

All No headache Headache

P valuesN = 1914 N = 850 N = 1064

Demographic

Mean age (years) 451 plusmn 134 453 plusmn 144 450 plusmn 125 0610

Ratio of womenmen 393607 300700 468532 lt0001

Current smoking () 486 521 458 0006

BMI (kgm2) 248 (223ndash277) 250 (225ndash281) 247 (222ndash275) 0018

Cardiac

SBP (mm Hg) 175 (156ndash200) 172 (152ndash197) 177 (160ndash202) lt0001

DBP (mm Hg) 104 plusmn 20 101 plusmn 21 107 plusmn 20 lt0001

PP (mm Hg) 72 (60ndash88) 74 (60ndash88) 72 (60ndash88) 0640

Target organ damage

ECG-LVH () 194 180 205 0192

Albuminuria () 41 32 49 0061

Hypertensive retinopathy ()

All grades 610 571 641 0002

Grades 3ndash4 139 111 162 lt0001

Medical history

Diabetes () 134 154 117 0019

History of heart failure () 104 102 105 0836

Coronary diseasea () 61 52 68 0147

Peripheral artery disease () 27 29 24 0502

Previous stroke () 84 88 81 0562

Antihypertensive treatment () 466 461 469 0734

Etiologies ()

Essential hypertension 816 849 789 0001

Renal artery stenosis 37 26 46 0020

Primary aldosteronism 20 18 23 0450

Renal parenchymal disease 78 64 90 0031

Pheochromocytoma 10 11 10 0766

Aortic coarctation 17 18 16 0777

Miscellaneous 21 15 26 0049

Biochemical

eGFR (mlmin) 824 (664ndash987) 844 (664ndash1010) 810 (664ndash969) 0029

Total cholesterol (gl) 220 (200ndash250) 220 (190ndash250) 220 (200ndash250) 0205

Data are mean plusmn SD or median (interquartile range) unless otherwise stated P values indicate significance levels between groups Abbreviations BMI body mass index DBP diastolic blood pressure ECG-LVH electrocardiogram-left ventricular hypertrophy eGFR esti-mated glomerular filtration rate PP pulse pressure SBP systolic blood pressure

aExcept heart failure

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considered as a warning sign but not as a sign of poor out-come provided that the patients are correctly monitored

Janeway was the first to describe the link between hyper-tension and headache in 1913 individuals5 Headache is prob-ably the most classical symptom in relation to hypertension with current hypertension guidelines still recommending questioning for headache during the work-up of a hyperten-sive patient2 However the presence of headache has no prac-tical consequence for the management of hypertension with the exception of a hypertensive crisis associated with neuro-logical signs suggestive of hypertensive encephalopathy

The classification of headache has moreover changed over the past decades The current classification proposed by the IHS3 describes different subtypes of headache migraine tension-type headache cluster headache other primary headaches and secondary headaches Headaches attributed to arterial hypertension belong to secondary headaches in which different clinical settings are described pheochro-mocytoma hypertensive crisis with or without hypertensive encephalopathy preeclampsia and eclampsia In the present cohort certain data used in the IHS classification were not available Thus a classification was implemented enabling

to differentiate as accurately as possible patients suffering from migraine (M) from those with frequent symptoms (DH) and those with other types of headache (OH)

The first question at issue is whether headache repre-sents a marker of hypertension severity Conflicting results have been reported regarding the relationship between headache and BP level Some studies did not find any rela-tionship between BP and headache or tension-type head-ache1314 while others demonstrated a positive relationship in hypertensive patients1516 With regard to migraine specifi-cally such association is also controversial with both posi-tive17ndash19 and negative results being reported20 The present study showed a positive association between diastolic BP and all types of headache even after extensive adjustment In keeping with this result randomized controlled trials have demonstrated a decrease in headache frequency with beta blockers thiazide diuretics angiotensin receptor block-ers and angiotensin-converting enzyme inhibitors152122 Calcium channel blockers were the only class that did not demonstrate any improvement of this symptom15 Hence the interpretation of this symptom is likely complex and modified by the patientrsquos knowledge of his or her BP levels23

Table 2 Multivariate logistic regression analysis of study variables according to headache type

Variable

Headache (all) Migraine ldquoDaily headacherdquo ldquoOther headacherdquo

OR (95 CI) P value OR (95 CI) P value OR (95 CI) P value OR (95 CI) P value

Gender (women) 209 (172ndash254) lt0001 407 (294ndash564) lt0001 157 (121ndash205) 0001 NS NS

SBP + 10 mm Hg NS NS NS NS NS NS NS NS

DBP + 10 mm Hg 113 (108ndash118) lt0001 112 (104ndash120) 0004 110 (103ndash117) 0007 105 (100ndash110) 0034

BMI NS NS 097 (093ndash100) 0049 NS NS NS NS

Diabetes 064 (048ndash084) 0001 NS NS NS NS 062 (046ndash085) 0003

Retinopathy (yes) NS NS NS NS NS NS NS NS

Retinopathy (grade 3ndash4) 132 (098ndash179) 0072 NS NS 176 (123ndash252) 0002 NS NS

Primary hypertension 077 (060ndash099) 0046 NS NS NS NS NS NS

Smokers (yes) NS NS NS NS NS NS NS NS

Abbreviations BMI body mass index 95 CI 95 confidence interval DBP diastolic blood pressure NS nonsignificant OR odds ratio SBP systolic blood pressure

Figure 2 Survival curves relative to the presence or absence of headache in the entire cohort (N = 1914 P for log rank)

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Courand et al

In addition to the association with BP level our study demonstrated that headache was associated with an increased prevalence of all grades as well as severe hyperten-sive retinopathy (641 and 162 respectively) Moreover we observed an independent association of DH with this subclinical target organ damage even after exclusion of patients with putative malignant hypertension Since hyper-tensive retinopathy has recently shown its ability to pre-dict stroke and other cardiovascular outcomes the present

finding argues in favor of a fundus examination in hyperten-sive patients suffering from headache24ndash27

The second important question is whether headache car-ries a poor prognostic significance over the long term

While this question has been addressed in the general popu-lation it has not been assessed in hypertensive patients In par-ticular a recent meta-analysis found a 2-fold increased risk of ischemic stroke among individuals with a history of migraine with aura On the other hand there was no association between

Table 3 Cox regression models in multivariate analysis at 30 years of follow-up (N = 1848)

All-cause death Cardiovascular death Stroke death

HR (95 CI) P value HR (95 CI) P value HR (95 CI) P value

Model 1 2-subgroup analysis

Headache (yes vs no) 082 (073ndash093) 0002 080 (068ndash095) 0011 100 (070ndash143) 0993


Daily headache vs other headache 083 (068ndash101) 0057 089 (069ndash116) 0386 074 (044ndash125) 0262

Daily headache vs migraine 085 (065ndash111) 0230 078 (055ndash110) 0154 095 (046ndash198) 0894

Daily headache vs no headache 073 (061ndash087) lt0001 073 (057ndash093) 0010 084 (051ndash140) 0506

Migraine vs other headache 098 (077ndash125) 0865 112 (082ndash154) 0485 078 (040ndash153) 0469

Migraine vs no headache 085 (067ndash108) 0178 093 (069ndash127) 0659 089 (046ndash172) 0721

Other headache vs no headache 087 (075ndash100) 0052 083 (068ndash102) 0073 114 (076ndash171) 0542










Model 1 adjusted for age sex systolic blood ressure (BP) diastolic BP diabetes total cholesterol smoking status Modification of Diet in Renal Disease antihypertensive treatment previous cardiovascular disease primary hypertension and body mass index Model 2 adjusted for the same variables and hypertensive retinopathy electrical left ventricular hypertrophy and albuminuria Abbreviations 95 CI 95 confi-dence interval HR hazard ratio

Figure 3 Survival curves relative to the subtypes of headache (N = 1064 P for the Cox regression model adjusted for age)

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migraine and myocardial infarction or death due to cardio-vascular disease28 A recent cross-sectional survey indicated that the prevalence of comorbidity hypertensionndashmigraine is substantial and that patient with comorbidity had more fre-quently a history of stroketransient ischemic attack in com-parison to hypertensive patients without migraine (44 vs 31)29 However this study presents some limitations namely the limited number of cerebrovascular events and the impos-sibility to analyze the causality between the onset of hyperten-sionndashmigraine and cerebrovascular events

The prognostic value of headache in moderate to severe hypertensive patients has never been tested to date In the present analysis conducted in a large cohort with a very long follow-up we demonstrate that the presence of headache was not associated with worse outcome with regard to all-cause and cardiovascular mortality in both univariate and multivar-iable analysis In fact headache appeared to carry a protective effect which was also true for the most symptomatic patients ie those belonging to the DH subgroup Conversely we did not find any association with stroke mortality although the number of events was relatively low in this instance thus precluding any firm conclusion At first glance this result regarding hard endpoints appears somewhat paradoxical given that patients with headache had higher BP and more frequent subclinical target organ damage (namely hyperten-sive retinopathy and altered renal function) at baseline than those without headache One could speculate that headache constituted a warning symptom both for patients and physi-cians thereby converting the ldquosilent killerrdquo in a symptomatic disease It is likely that such symptomatic patients were more closely monitored and also more aggressively treated for their hypertension or other risk factors albeit impossible to prove in the absence of any information relative to the temporal trends of BP and the use of medications Treatment compli-ance would also likely be higher in symptomatic hypertensive patients since antihypertensive treatment has a direct benefit on headache relief22 On the other hand patients without headache with a ldquosilentrdquo disease might have been more reluc-tant to visit their physician than symptomatic patients and thus with less opportunity to achieve BP control3031

Study limitations

Certain data currently used for the diagnosis of migraine by the IHS diagnostic criteria3 were not assessed in the ques-tionnaire (presence of aura sensitivity to light or sound pulsing characteristic of the headache) This omission may have induced a misclassification of some patients in our vari-ous subgroups of headache However the same trend for a protective effect was observed for all subgroups of headache in comparison to patients without this symptom and thus it is likely that a reclassification of some patients from one sub-group of headache to another would not have modified this finding Moreover residual confounding due to measured or unmeasured bias might exist despite the adjustment we per-formed (frequency of visits achievement of BP control dur-ing the follow-up incidence of other risk factors) Therefore no information was available regarding obstructive sleep apnea in our cohort which could be a confounder explain-ing both headache and the conveying of a negative impact

on cardiovascular prognosis32 Moreover no information was available concerning nonsteroidal anti-inflammatory drugs treatment or self-medication One can assume that the use of each sort of nonsteroidal anti-inflammatory drugs (those protective like aspirin and those having a negative impact on cardiovascular prognosis) was probably balanced and would not account by its own for the protective effect of headache Another aspect is that such use is expected to be discontinuous in headache while to exert a protective or a negative effect drugs should be taken on a long-term basis33 Nevertheless because of this negative impact the presence of these sleep apneas or nonsteroidal anti-inflammatory drugs use would have likely weakened the ldquoprotectiverdquo effect of headache and removing these confounders would have increased the strength protective association we identified between headaches and outcome

In moderate to severe hypertensive subjects the present results demonstrate that headache is more frequently associ-ated with high BP level and subclinical target organ damage namely hypertensive retinopathy While recent guidelines do not propose a systematic screening of hypertensive retin-opathy in all hypertensive patients2 such screening would appear nonetheless appropriate in those patients presenting with headache thus enabling to stratify their risk profile

Specific subtypes of headache (migraine or tension-type headache) must be carefully identified and referred to specialists in order to implement appropriate treatment Hypertensive patients with nonspecific headache should be reassured by their physicians as this symptom is not an indi-cation of an increased risk over the long term The fact that the ldquokillerrdquo is no longer silent is likely a strong argument to motivate both the physician and the patient to control BP the 2 major ingredients in improving prognosis

SUPPLEMENTARY MATERIAL

Supplementary materials are available at American Journal of Hypertension (httpajhoxfordjournalsorg)

ACKNOWLEDGMENTS

The authors would like to recall the memory of Pr Alain Froment who played a major role in the generation of the cohort No external funding was provided to the authorsrsquo affiliations

DISCLOSURE

The authors declared no conflict of interest

REFERENCES

1 Mancia G Blood pressure reduction and cardiovascular outcomes past present and future Am J Cardiol 2007 1003Jndash9J

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Courand et al

2 2013 practice guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) ESHESC Task Force for the Management of Arterial Hypertension J Hypertens 2013 311925ndash1938

3 The international classification of headache disorders 2nd edition Headache Classification Subcommittee of the International Headache Society Cephalalgia 2004 24(Suppl 1)9ndash160

4 Schuumlrks M Rist PM Bigal ME Buring JE Lipton RB Kurth T Migraine and cardiovascular disease systematic review and meta-analysis BMJ 2009 339b3914

5 Janeway TC A clinical study of hypertensive cardiovascular disease Arch Intern Med 1913 12755ndash798

6 Zampaglione B Pascale C Marchisio M Cavallo-Perin P Hypertensive urgencies and emergencies Prevalence and clinical presentation Hypertension 1996 27144ndash147

7 Courand PY Milon H Gustin MP Froment A Bricca G Lantelme P Effect modification of aortic atheroma on the prognostic value of heart rate in hypertension J Hypertens 2013 31484ndash491

8 Courand PY Milon H Bricca G Khettab F Lantelme P Diastolic blood pressure aortic atheroma and prognosis in hypertension new insights into a complex association Atherosclerosis 2014 233300ndash306

9 Harbaoui B Courand PY Defforges A Khettab F Milon H Girerd N Lantelme P Cumulative effects of several target organ damages in risk assessment in hypertension Am J Hypertens 2016 29234ndash244

10 Comiteacute consultatif sur le traitement de lrsquoinformation en matiegravere de recherche dans le domaine de la santeacute httpwwwenseignementsupre-cherche gouvfrcid20537cctirshtml Accessed 2010

11 Keith NM Wagener HP Barker NW Some different types of essen-tial hypertension their course and prognosis Am J Med Sci 1974 268336ndash345

12 Pavillon G Laurent F Certification et classification des causes de deacutecegraves BEH 2003 30ndash31134ndash138

13 Weiss NS Relation of high blood pressure to headache epistaxis and selected other symptoms The United States Health Examination Survey of Adults N Engl J Med 1972 287190ndash194

14 Bensentildeor IJ Lotufo PA Mion D Jr Martins MA Blood pressure behav-iour in chronic daily headache Cephalalgia 2002 22190ndash194

15 Cooper WD Glover DR Hormbrey JM Kimber GR Headache and blood pressure evidence of a close relationship J Hum Hypertens 1989 341ndash44

16 Bulpitt CJ Dollery CT Carne S Change in symptoms of hypertensive patients after referral to hospital clinic Br Heart J 1976 38121ndash128

17 Bigal ME Kurth T Santanello N Buse D Golden W Robbins M Lipton RB Migraine and cardiovascular disease a population-based study Neurology 2010 74628ndash635

18 Scher AI Terwindt GM Picavet HS Verschuren WM Ferrari MD Launer LJ Cardiovascular risk factors and migraine the GEM popula-tion-based study Neurology 2005 64614ndash620

19 Entonen AH Suominen SB Korkeila K Maumlntyselkauml PT Sillanmaumlki LH Ojanlatva A Rautava PT Koskenvuo MJ Migraine predicts

hypertensionndasha cohort study of the Finnish working-age population Eur J Public Health 2014 24244ndash248

20 Wiehe M Fuchs SC Moreira LB Moraes RS Fuchs FD Migraine is more frequent in individuals with optimal and normal blood pressure a population-based study J Hypertens 2002 201303ndash1306

21 Hansson L Smith DH Reeves R Lapuerta P Headache in mild-to-moderate hypertension and its reduction by irbesartan therapy Arch Intern Med 2000 1601654ndash1658

22 Law M Morris JK Jordan R Wald N Headaches and the treatment of blood pressure results from a meta-analysis of 94 randomized placebo-controlled trials with 24000 participants Circulation 2005 1122301ndash2306

23 Stewart McD G Headache and hypertension Lancet 1953 11261ndash1266 24 Mitchell P Wang JJ Wong TY Smith W Klein R Leeder SR Retinal

microvascular signs and risk of stroke and stroke mortality Neurology 2005 651005ndash1009

25 Witt N Wong TY Hughes AD Chaturvedi N Klein BE Evans R McNamara M Thom SA Klein R Abnormalities of retinal microvas-cular structure and risk of mortality from ischemic heart disease and stroke Hypertension 2006 47975ndash981

26 Wong TY Klein R Couper DJ Cooper LS Shahar E Hubbard LD Wofford MR Sharrett AR Retinal microvascular abnormalities and incident stroke the Atherosclerosis Risk in Communities Study Lancet 2001 3581134ndash1140

27 Wong TY Klein R Sharrett AR Duncan BB Couper DJ Tielsch JM Klein BE Hubbard LD Cerebral white matter lesions retinopathy and incident clinical stroke JAMA 2002 28867ndash74

28 Rose KM Wong TY Carson AP Couper DJ Klein R Sharrett AR Migraine and retinal microvascular abnormalities the Atherosclerosis Risk in Communities Study Neurology 2007 681694ndash1700

29 Mancia G Rosei EA Ambrosioni E Avino F Carolei A Daccograve M Di Giacomo G Ferri C Grazioli I Melzi G Nappi G Pinessi L Sandrini G Trimarco B Zanchin G MIRACLES Study Group Hypertension and migraine comorbidity prevalence and risk of cerebrovascular events evidence from a large multicenter cross-sectional survey in Italy (MIRACLES study) J Hypertens 2011 29 309ndash318

30 Redfern J Menzies M Briffa T Freedman SB Impact of medical con-sultation frequency on modifiable risk factors and medications at 12 months after acute coronary syndrome in the CHOICE randomised controlled trial Int J Cardiol 2010 145481ndash486

31 Godwin M Birtwhistle R Seguin R Lam M Casson I Delva D MacDonald S Effectiveness of a protocol-based strategy for achiev-ing better blood pressure control in general practice Fam Pract 2010 2755ndash61

32 Russell MB Kristiansen HA Kvaeligrner KJ Headache in sleep apnea syndrome epidemiology and pathophysiology Cephalalgia 2014 34752ndash755

33 Bousser MG Welch KM Relation between migraine and stroke Lancet Neurol 2005 4533ndash542

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Courand et al

regard to the presence and characteristics of headache were excluded from the study resulting in a total of 1914 hyper-tensive patients being included in the present analysis Oral consent was obtained from every patient in accordance with French regulations prevailing at the time The study received approval of the Commission Nationale Informatique et Liberteacute (CNIL) Under French law as mentioned in sev-eral published technical notes in keeping with European directives10 only the approval of the CNIL is required for single-center observational usual care studies such as that performed herein The vital status query was approved by national authorities prior to data extraction by the Institut National de la Statistique et des Etudes Economiques

Baseline work-up

A special form was completed for every patient the con-tents of which included various morphometric characteris-tics risk factors for cardiovascular events (smoking status alcohol intake salt consumption etc) history of cardiovas-cular disease and current medication and symptoms

Smoking status was based on current tobacco consump-tion or stopped within the last 5 years BP was measured with a manual sphygmomanometer in supine position The considered systolic BP diastolic BP and pulse pressure were the mean of 6 measurements Twelve-lead electrocardiogram was performed in the supine position An ophthalmoscopic fundus examination of the right eye was performed after pharmacological pupil dilation to detect signs of hyperten-sive retinopathy Classification of hypertensive retinopathies was performed by 2 trained cardiologists according to the 4-grade classification of Keith Wagener and Barker largely used at that time11

An overnight fasting blood sample was drawn for hemo-gram and plasma measurements (electrolytes creatinine glucose and total cholesterol) Diabetes was retrospectively defined by either a fasting glucose ge126 gl (ge79 mmoll) on 2 separate occasions or a current use of antidiabetic medica-tion Renal function was estimated using the Modification of Diet in Renal Disease (MDRD) formula

Previous cardiovascular diseases included the history of heart failure (clinical or chest radiographic findings such as dyspnea edema cardiomegaly or pulmonary congestion)

coronary artery disease (clinical findings such as angina pectoris or myocardial infarction or Q wave on electrocar-diogram) peripheral arterial disease (walking impairment or pain at rest) and stroke (clinical findings) Target organ damage was defined according to the following electri-cal left ventricular hypertrophy in case of a Sokolow index gt35 mV presence of albuminuria if gt300 mgday and hypertensive retinopathy (including all grades from 1 to 4 or only advanced retinopathy including grades 3 and 4)2 Malignant hypertension was defined according to the pres-ence of grade 3 or 4 hypertensive retinopathy and diastolic BP gt130 mm Hg2

Assessment of headache

All patients were carefully questioned at baseline by 2 trained physicians regarding their history of headaches The first question was ldquoDo you often experience headacherdquo (ie at least twice during the past year) If the answer was ldquoyesrdquo the patient was categorized as having headache and had to answer the following standardized items (i) the local-ization of the headache (unilateral or bilateral) (ii) the con-comitant presence of other symptoms including nausea and vomiting (iii) the intensity of the headache (severe or mild) and (iv) the frequency of headache per week The following classification of headaches was retained as derived from the International Headache Society (IHS) diagnostic criteria3

1 Migraine inclusion criteria required at least 2 of the fol-lowing itemsmdashsevereunilateralassociated with nausea or vomiting Exclusion criteria mainly consisted in the presence of daily headache

2 Daily headache patients with daily symptoms3 Other headache patients with headache not included in

the previous 2 categories

Hence patients from our cohort were divided into 4 sub-groups no headache (NH) migraine (M) daily headache (DH) and other headache (OH)

Assessment of outcomes

Deaths at 30 years of follow-up were obtained from the Reacutepertoire National drsquoIdentification des Personnes Physiques (RNIPP a directory maintained by the Institut National de la Statistique et des Etudes Economiques INSEE) Causes of death were coded from the death certificates as provided by INSERM SC8 according to the International Classification of Diseases Ninth Revision

The end points used in this study were all-cause deaths (cardiovascular and noncardiovascular including sudden death) cardiovascular deaths (from cerebrovascular dis-ease myocardial infarction or heart failure) and stroke deaths as classified by the French national CeacutepiDC (Centre drsquoEpideacutemiologie sur les Causes Meacutedicales de Deacutecegraves)12

Statistical analyses

Continuous variables with near-normal distributions are expressed as mean plusmn SD Continuous variables with skewed

Figure 1 Flowchart summarizing the generation of the study cohort

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RESULTS






Survival analysis







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Courand et al


DISCUSSION



Characteristics


P valuesN = 1914 N = 850 N = 1064

Demographic





Cardiac




Target organ damage

ECG-LVH () 194 180 205 0192

Albuminuria () 41 32 49 0061


All grades 610 571 641 0002

Grades 3ndash4 139 111 162 lt0001

Medical history

Diabetes () 134 154 117 0019






Etiologies ()








Biochemical





Dow











Variable














Dow




Courand et al




























Dow







Study limitations







ACKNOWLEDGMENTS


DISCLOSURE


REFERENCES


Dow




Courand et al


































Dow











RESULTS






Survival analysis







Dow




Courand et al


DISCUSSION



Characteristics


P valuesN = 1914 N = 850 N = 1064

Demographic





Cardiac




Target organ damage

ECG-LVH () 194 180 205 0192

Albuminuria () 41 32 49 0061


All grades 610 571 641 0002

Grades 3ndash4 139 111 162 lt0001

Medical history

Diabetes () 134 154 117 0019






Etiologies ()








Biochemical





Dow











Variable














Dow




Courand et al




























Dow







Study limitations







ACKNOWLEDGMENTS


DISCLOSURE


REFERENCES


Dow




Courand et al


































Dow




Courand et al


DISCUSSION



Characteristics


P valuesN = 1914 N = 850 N = 1064

Demographic





Cardiac




Target organ damage

ECG-LVH () 194 180 205 0192

Albuminuria () 41 32 49 0061


All grades 610 571 641 0002

Grades 3ndash4 139 111 162 lt0001

Medical history

Diabetes () 134 154 117 0019






Etiologies ()








Biochemical





Dow











Variable














Dow




Courand et al




























Dow







Study limitations







ACKNOWLEDGMENTS


DISCLOSURE


REFERENCES


Dow




Courand et al


































Dow











Variable














Dow




Courand et al




























Dow







Study limitations







ACKNOWLEDGMENTS


DISCLOSURE


REFERENCES


Dow




Courand et al


































Dow




Courand et al




























Dow







Study limitations







ACKNOWLEDGMENTS


DISCLOSURE


REFERENCES


Dow




Courand et al


































Dow







Study limitations







ACKNOWLEDGMENTS


DISCLOSURE


REFERENCES


Dow




Courand et al


































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Courand et al


































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The Paradoxical Significance of Headache in Hypertension

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